Section 3 of 6
Product information and disease description
723 evidence topics · 263 sources
Product description
Phase of product development
Regulatory submission: BLA planned for late 2028
Investigational status as of October 2026
Current phase: pivotal phase 2 trial with cohort 4 enrolling (October 2026)
Enrollment completion announced in September 2024 under the original design (history; the pivotal population was redefined in 2026 as the 12 participants of cohort 4)
Phase 1 trial: seven participants treated, trial completed, long-term follow-up ongoing
IND clearance in January 2019 and Fast Track designation in February 2019
FDA orphan drug designation: designated 1 February 2019
| Field | Quoted record |
|---|---|
| Generic name | “Adeno-associated virus serotype 9 vector containing the human lysosome-associated membrane glycoprotein 2 isoform B transgene (AAV9.LAMP2B)” |
| Date designated | “02/01/2019” |
| Orphan designation | “Treatment of Danon Disease” |
| Orphan designation status | “Designated” |
| FDA orphan approval status | “Not FDA Approved for Orphan Indication” |
| Sponsor | “Rocket Pharmaceuticals, Inc.” |
Rare pediatric disease designation: held by January 2023, grant date not stated
Regenerative medicine advanced therapy designation: announced 7 February 2023
Benefits of RMAT designation as the company describes them
EMA PRIME eligibility: entry in the EMA list of medicines in the PRIME scheme (date of granting 25 May 2023)
| Field | Quoted record |
|---|---|
| Name | “RP-A501” |
| Substance type | “Advanced Therapy Medicinal Product” |
| Therapeutic area | “Cardiovascular Diseases” |
| Therapeutic indication | “Treatment of Danon disease” |
| Type of data supporting request | “Non-clinical + Clinical exploratory” |
EMA PRIME designation: company announcement of 31 May 2023
EU orphan designation EU/3/23/2826: designated 16 August 2023
| Field | Quoted record |
|---|---|
| Active substance | “adeno-associated virus serotype 9 vector containing the human LAMP2 isoform B transgene” |
| Intended use | “Treatment of Danon disease” |
| Orphan designation status | “Positive” |
| EU designation number | “EU/3/23/2826” |
| Date of designation | “16/08/2023” |
| Sponsor | “Rocket Pharmaceuticals B.V.” |
EU classification as an advanced therapy medicinal product (Committee for Advanced Therapies recommendation dated 15 June 2023)
| Field | Quoted record |
|---|---|
| Public description of active substance | “Recombinant Adeno-associated virus serotype 9 vector containing the human-lysosome-associated membrane glycoprotein 2 isoform B transgene (AAV9.LAMP2B)” |
| Indication | “Treatment of Danon Disease” |
| Classification conclusion | “the EMA/CAT considers that the Product falls within the definition of a gene therapy medicinal product.” |
EMA paediatric investigation plan: decision P/0004/2025 of 27 January 2025
| Field | Quoted record |
|---|---|
| Decision number | “P/0004/2025” |
| PIP number | “EMEA-003639-PIP01-24” |
| Decision type | “P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)” |
| Decision date | “27/01/2025” |
| Condition or indication | “Treatment of Danon Disease” |
Designations held as the company lists them in 2026
Clinical hold of May 2021 on the phase 1 trial (announced 10 May 2021): FDA request for protocol changes
Clinical hold of 2021: discontinuation of the higher dose by agreement with FDA (August 2021)
Lifting of the 2021 hold: announced 16 August 2021
Safety measures added to the protocols after the phase 1 high-dose experience
Clinical hold of 23 May 2025 on the phase 2 trial: announcement of 27 May 2025
Clinical hold of 2025: root cause focus stated on 27 May 2025
Clinical hold of 2025: two participants with capillary leak syndrome and the conclusion of the investigation, as stated in 2026 filings
Lifting of the 2025 hold: announced 20 August 2025
Conditions of resumption after the 2025 hold: recalibrated dose, sequential dosing, and revised immunomodulation
Resumption of dosing after the 2025 hold: guidance of November 2025 and status in May and August 2026
FDA end-of-phase 1 meeting: registration path announced 22 December 2022
FDA alignment of September 2023 on the pivotal design (original design at 6.7 × 10¹³ GC/kg, later modified)
FDA alignment of September 2026 on completing the pivotal trial
Accelerated approval path: endpoints confirmed by FDA in September 2026
Efficacy success criterion for the pivotal cohort (October 2026)
Company timeline as of October 2026: dosing completion mid-2027 and topline results mid-2028
“9 additional patients in Cohort 4” (opens the source at this quote in a new tab)
“MID-2027 Dosing completion” (opens the source at this quote in a new tab)
“MID-2028 TOPLINE TARGET” (opens the source at this quote in a new tab)
“Primary efficacy readout from pivotal Cohort 4” (opens the source at this quote in a new tab)
Company caveats on the approval pathway (October 2026)
Priority review voucher: eligibility stated by the company
Priority review voucher: sunset date of the rare pediatric disease voucher program
Priority review voucher: sale of the voucher issued with the approval of Kresladi (company precedent)
License from the University of California, San Diego (February 2017)
License from REGENXBIO for the NAV AAV9 vector (November 2018)
July 2025 reorganization: resources concentrated on the cardiovascular AAV programs, including Danon disease
Funding of the program: cash runway stated in October 2026
Funding of the program: loan terms tied to FDA approval of a BLA for RP-A501
Funding of the program: California Institute for Regenerative Medicine grant
Product information
Generic, brand name and therapeutic class of product
Manufacturer: Rocket Pharmaceuticals
European applicant: Rocket Pharmaceuticals B.V.
Development code and descriptive name in the trial registry
Name in the phase 1 publication
Active substance wording used by EMA
Generic name in the FDA orphan drug designation record
Name under which EMA lists the product in the PRIME scheme
LAMPLIGHT study branding
| Record | Quoted identifier |
|---|---|
| Sponsor protocol number, phase 2 trial | “RP-A501-0123” |
| Other identifier, phase 2 trial | “LAMPLIGHT-2” |
| Record | Quoted identifier |
|---|---|
| Sponsor protocol number, phase 1 trial | “RP-A501-0219” |
| Other identifier, phase 1 trial | “LAMPLIGHT-1” |
International nonproprietary name, United States adopted name, and brand name
No evidence found.
Therapeutic class: AAV9-based gene therapy
Intervention type in the trial registry
Dosage forms and strengths
Vector and transgene: AAV9 capsid containing the human LAMP2B transgene
Expression cassette of the AAV9.LAMP2B vector in the preclinical mouse study: CAG promoter, WPRE, and AAV2 inverted terminal repeats
Promoter and expression cassette of the clinical product RP-A501
No evidence found.
Pharmaceutical form and route of administration
| Field | Quoted record |
|---|---|
| Pharmaceutical form | “Solution for infusion” |
| Route of administration | “Intravenous use” |
Dose unit and doses in the phase 2 trial: genome copies per kilogram
Doses in the phase 1 trial
Dose unit as written in other company documents: gc/kg and vg/kg
Recalibrated dose of 3.8 × 10¹³ GC/kg: relation to the full capsid content of the current drug product
Recalibrated dose: rationale stated when the 2025 hold was lifted
Numerical full-to-empty capsid ratio of the phase 1 and phase 2 drug product
No evidence found.
Nonclinical bridging of phase 2 material at the recalibrated dose
Manufacturing site and process: in-house production at Cranbury, New Jersey, with a HEK-293 cell-based process
In-house batches compared with phase 1 material (January 2023)
FDA positions on the manufacturing process reported in January 2023
Drug product supply for the pivotal trial (September 2023)
Production of the vector used in the preclinical mouse study
Commercial presentation, concentration, fill volume, storage, and packaging
No evidence found.
Average sales price and wholesale acquisition cost
Not applicable.
American hospital formulary service (AHFS), or other drug classification
AHFS Pharmacologic-Therapeutic Classification, Anatomical Therapeutic Chemical code, and USP category assigned to RP-A501
No evidence found.
EU classification: gene therapy medicinal product
| Field | Quoted record |
|---|---|
| Public description of active substance | “Recombinant Adeno-associated virus serotype 9 vector containing the human-lysosome-associated membrane glycoprotein 2 isoform B transgene (AAV9.LAMP2B)” |
| Indication | “Treatment of Danon Disease” |
| Classification conclusion | “the EMA/CAT considers that the Product falls within the definition of a gene therapy medicinal product.” |
| Outcome of classification | “GTMP” |
EMA PRIME list: substance type and therapeutic area
| Field | Quoted record |
|---|---|
| Substance type | “Advanced Therapy Medicinal Product” |
| Therapeutic area | “Cardiovascular Diseases” |
EMA paediatric investigation plan: therapeutic area
FDA regenerative medicine advanced therapy designation: eligibility definition quoted by the company
Regulatory product class in the United States: biologic reviewed under a Biologics License Application
ICD-10-CM code for the disease: E74.05, which the company states it secured in 2023
| Index entry | Quoted record |
|---|---|
| Deficiency term | “lysosome-associated membrane protein 2 [LAMP2]” |
| Code | “E74.05” |
Indication
Regulatory approval status: no approved indication
Indication under development: cardiomyopathy associated with Danon disease
Initial population the company states it will address (October 2026): males with symptomatic hypertrophic cardiomyopathy
Label expansions the company describes (October 2026): earlier treatment of males and treatment of females
Pivotal trial population: males aged 8 years or older with left ventricular hypertrophy and preserved systolic function
Exclusion of end-stage heart failure after the phase 1 experience
EMA paediatric investigation plan: condition and paediatric subset covered
EMA paediatric investigation plan: waiver from birth to less than 3 years of age
EMA paediatric investigation plan: studies planned in males aged 3 to less than 8 years and in females
Pharmacology
Mechanism of action
Product composition: AAV9 capsid carrying a full-length wild-type human LAMP2B transgene
Intended effect: restoration of LAMP2B protein expression and repair of autophagy
Autophagic defect the product is designed to correct
Rationale for the AAV9 capsid: cardiac tropism
Rationale for the B isoform: predominant LAMP2 isoform in cardiomyocytes
Rationale for the B isoform: requirement for autophagosome-lysosome fusion in human cardiomyocytes
Expression cassette and promoter
Single administration and the durability rationale in non-dividing cardiomyocytes
Absence of an opportunity to re-dose
Pharmacodynamics
Preclinical pharmacology: dose-dependent LAMP2B protein restoration in the Lamp2 knockout mouse
Preclinical pharmacology: restoration of autophagic flux
Preclinical pharmacology: cardiac contraction and relaxation in treated mice
Preclinical pharmacology: survival in treated mice
Preclinical pharmacology: threshold dose for cardiac efficacy in the mouse model
Preclinical pharmacology: durability of transgene expression in mouse myocardium
Preclinical pharmacology: hepatic and skeletal muscle effects in the mouse model
Limitations of the mouse model for pharmacodynamic assessment
Preclinical pharmacology: transgene protein expression in non-human primate heart
Human induced pluripotent stem cell cardiomyocyte models: rescue by LAMP2B replacement
Mouse bridging data for the recalibrated 3.8 × 10¹³ GC/kg dose
Human pharmacodynamic markers assessed in the clinical program
Grading scale for myocardial LAMP2 protein expression by immunohistochemistry
Myocardial LAMP2B protein expression by immunohistochemistry in the phase 1 adult cohorts, week 8 and month 12
| Cohort and participant | Dose | Week 8 | Month 12 |
|---|---|---|---|
| Adult low dose, 1001 | “6.7 x 10¹³ GC/kg” | “7.3%” | “2.5% (Previously <15%)” |
| Adult low dose, 1002 | “6.7 x 10¹³ GC/kg” | “36.9%” | “67.8%” |
| Adult low dose, 1005 | “6.7 x 10¹³ GC/kg” | “17.6%” | “92.4%” |
| Adult high dose, 1006 | “1.1 x 10¹⁴ GC/kg” | “5.0%” | “100%” |
| Adult high dose, 1007 | “1.1 x 10¹⁴ GC/kg” | “6.9%” | “100%” |
Relationship between immunomodulation compliance and myocardial transgene expression
Dose relationship of myocardial LAMP2 expression: expression at the low dose and above
Durability of myocardial LAMP2 protein expression and of vector-derived nucleic acid
Pharmacodynamic response in myocardial tissue: reduction in autophagic vacuolar area
Time to onset of the pharmacodynamic and structural response
Pharmacokinetics
Conventional pharmacokinetic characterization
No evidence found.
Preclinical biodistribution: vector genomes by tissue in the mouse
Preclinical biodistribution: vector copy number and transcript by tissue in non-human primates
Cardiac vector copy number in phase 1 participants, week 8 and month 12
Cardiac vector copy number in an explanted heart five months after infusion
Cardiac vector DNA by quantitative polymerase chain reaction through month 36
Persistence of vector genomes and transcripts in myocardium through 60 months
Vector shedding in body fluids
No evidence found.
Pre-existing anti-AAV9 neutralizing antibodies: eligibility threshold in both trials
Pre-existing anti-AAV9 immunity in a participant with a serious immune-related event
Post-dose antibody responses to the capsid and to the transgene in preclinical species
Anti-LAMP2 antibody responses in the mouse model
Immunogenicity assessment planned in the clinical program
Post-dose anti-AAV9 and anti-LAMP2 antibody titers in treated participants
No evidence found.
Antibody kinetics after systemic AAV9 with and without rituximab and sirolimus, including Danon disease participants
Seroprevalence of anti-AAV9 neutralizing antibodies in a 10-country sample of adults and children
Variability of neutralizing antibody assays and eligibility cutoffs across programs
Pre-existing antibodies as a barrier to transduction, as stated in the preclinical report
Contraindications/Warnings/Precautions/Adverse effects
Warnings and precautions
Labeling status: investigational product with no approved prescribing information
Thrombotic microangiopathy: phase 1 participant at 1.1 × 10¹⁴ GC/kg, first report in December 2020
Thrombotic microangiopathy: grade and classification of the phase 1 event
Thrombotic microangiopathy: factors the sponsor associated with the phase 1 event, November 2021
Thrombotic microangiopathy: weight and total vector dose of phase 1 participant 1007
| Participant | Age at treatment | Dosing weight | Cohort dose | Total dose |
|---|---|---|---|---|
| 1007 | “20 y” | “96.7 kg” | “1.1 x 10¹⁴ GC/kg” | “1.06 x 10¹⁶ GC” |
Clinical hold on the phase 1 trial, May 2021
Discontinuation of the 1.1 × 10¹⁴ GC/kg dose, August 2021
Lifting of the phase 1 clinical hold, August 16, 2021
Risk mitigation adopted after the phase 1 high-dose event
“No further enrollment at HIGHER dose” (opens the source at this quote in a new tab)
“Corticosteroids: Limit daily dose” (opens the source at this quote in a new tab)
“Sirolimus: Minimize renal impact” (opens the source at this quote in a new tab)
“Frequent monitoring for early signs of TMA” (opens the source at this quote in a new tab)
“Rituximab continued” (opens the source at this quote in a new tab)
Serious adverse events of interest and platelet changes by phase 1 cohort, data cut September 27, 2022
| Measure | Low-dose adult cohort (6.7 × 10¹³ GC/kg) | High-dose adult cohort (1.1 × 10¹⁴ GC/kg) | Low-dose pediatric cohort (6.7 × 10¹³ GC/kg) |
|---|---|---|---|
| Serious adverse events of interest | “n=2 grade 3 steroid myopathy” | “n=1 grade 3 steroid myopathy”“n=1 grade 4 TMA” | “none” |
| Platelets | “n=2, Grade 1 decrease(to LLN range)” | “n=1, Grade 4 decrease” | “Remain in normal range” |
Platelet decreases and transaminase elevations in the phase 1 low-dose adult cohort
Complement and platelet monitoring in the phase 1 pediatric cohort
Thrombotic microangiopathy and renal events in the phase 2 trial by cohort, as of August 7, 2026
| Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%) | Cohorts 1 and 2, 6.7 × 10¹³ GC/kg (n=4) | Cohort 3, 6.7 × 10¹³ GC/kg with C3 inhibitor (n=2) | Cohort 4, 3.8 × 10¹³ GC/kg (n=3) |
|---|---|---|---|
| Participants with at least 1 event | “3 (75.0)” | “2 (100)” | “1 (33.3)” |
| Thrombotic microangiopathy | “2 (50.0)” | “1 (50.0)” | “0” |
| Acute kidney injury | “1 (25.0)” | “1 (50.0)” | “0” |
| Renal failure | “1 (25.0)” | “0” | “0” |
Phase 2 thrombotic microangiopathy cases before May 2025: analyst account of the company conference call
Capillary leak syndrome and death in the phase 2 trial: first disclosure, May 27, 2025
Capillary leak syndrome: two participants affected, with multi-organ damage
Capillary leak syndrome: timing of onset and exposure to the C3 inhibitor
Capillary leak syndrome: the added immune suppression agent
Capillary leak syndrome: conclusion of the investigation on cause, as stated in the February 2026 annual report
Capillary leak syndrome: mechanism proposed in a 2026 commentary
Serious events in the two phase 2 participants who received the C3 inhibitor regimen (cohort 3), as of August 7, 2026
| Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%) | Cohorts 1 and 2 (n=4) | Cohort 3 (n=2) | Cohort 4 (n=3) |
|---|---|---|---|
| Aplastic anemia | “0” | “1 (50.0)” | “0” |
| Disseminated intravascular coagulation | “0” | “1 (50.0)” | “0” |
| Cytokine release syndrome | “0” | “1 (50.0)” | “0” |
| Hypertransaminasaemia | “0” | “1 (50.0)” | “0” |
| Pneumothorax | “0” | “1 (50.0)” | “0” |
| Sepsis | “0” | “1 (50.0)” | “0” |
| Shock | “0” | “1 (50.0)” | “0” |
| Retroperitoneal hemorrhage | “0” | “1 (50.0)” | “0” |
Description of the fatal event in the October 2026 company release
Protocol changes when the phase 2 clinical hold was lifted, August 20, 2025
Safety in the first three participants dosed at 3.8 × 10¹³ GC/kg under the modified protocol: August and September 2026 statements
Safety in the first three participants dosed at 3.8 × 10¹³ GC/kg: follow-up through about 3 months, as of September 4, 2026
Platelet counts and soluble C5b-9 in the first three cohort 4 participants, as of September 4, 2026
Hepatic events in the phase 2 trial by cohort, as of August 7, 2026
| Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%) | Cohorts 1 and 2 (n=4) | Cohort 3 (n=2) | Cohort 4 (n=3) |
|---|---|---|---|
| Gamma-glutamyltransferase increased | “0” | “0” | “1 (33.3)” |
| Hepatic enzyme increased | “1 (25.0)” | “0” | “0” |
| Hypertransaminasaemia | “0” | “1 (50.0)” | “0” |
Hepatic laboratory findings in the phase 1 pediatric cohort
Transaminase elevation as a baseline feature of Danon disease in the phase 1 eligibility criteria
Corticosteroid-associated skeletal myopathy in phase 1
Changes to the immunomodulatory regimen during phase 1 and their stated reasons
Infection: events reported with RP-A501 and its immunomodulatory regimen
Infection: vaccination and infection-related eligibility criteria in the phase 1 protocol
Cardiac and neurologic serious events in phase 2 cohorts 1 and 2, as of August 7, 2026
| Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%) | Cohorts 1 and 2 (n=4) | Cohort 3 (n=2) | Cohort 4 (n=3) |
|---|---|---|---|
| Cardiac arrest | “1 (25.0)” | “0” | “0” |
| Posterior reversible encephalopathy syndrome | “1 (25.0)” | “0” | “0” |
| Rhabdomyolysis | “1 (25.0)” | “0” | “0” |
Troponin after infusion in the phase 1 pediatric cohort
Heart transplantation 5 months after infusion in the phase 1 participant with reduced ejection fraction: attribution, with baseline ejection fraction given as 32%
Heart transplantation 5 months after infusion: clinical course and explant findings presented in November 2021, with baseline ejection fraction given as 35%
“Diminished LV EF (35%)” (opens the source at this quote in a new tab)
“Markedly elevated LV filling pressure (PCWp 26 mmHg)” (opens the source at this quote in a new tab)
“Prior evidence of fibrosis on MRI” (opens the source at this quote in a new tab)
“Increased frequency of ventricular arrhythmias” (opens the source at this quote in a new tab)
“Heart transplant (Month 5)” (opens the source at this quote in a new tab)
“Severe fibrosis” (opens the source at this quote in a new tab)
“No evidence of inflammation” (opens the source at this quote in a new tab)
Second heart transplantation in a phase 1 participant, 4.8 years after infusion
Survival during phase 1 follow-up
Timing of serious adverse events after infusion in phase 1, data cut September 27, 2022
Dorsal root ganglion or sensory neuropathy findings with RP-A501
No evidence found.
Re-administration after anti-AAV9 antibody formation
Regulatory acknowledgment of long-term safety concerns in pediatric use
Class context, systemic AAV gene therapy: pooled incidence and timing of immune-mediated adverse events
Class context, onasemnogene abeparvovec (AAV9): thrombotic microangiopathy warning in the prescribing information
Class context, onasemnogene abeparvovec (AAV9): thrombocytopenia warning and platelet monitoring schedule
Class context, onasemnogene abeparvovec (AAV9): thrombotic microangiopathy case reports
Class context, fordadistrogene movaparvovec (AAV9) in Duchenne muscular dystrophy: complement activation and thrombotic microangiopathy
Class context, systemic AAV9: complement activation with corticosteroids alone compared with rituximab, sirolimus, and corticosteroids
Class context, systemic AAV: review of publicly reported thrombotic microangiopathy cases
Disease context: thrombotic microangiopathy after heart transplantation in a child with Danon disease
Class context, high-dose AAV9: fatal capillary leak syndrome in a participant with Duchenne muscular dystrophy
Class context, high-dose AAV9: fatal capillary leak syndrome under prednisolone and sirolimus prophylaxis
Class context: capillary leak, endothelial, and dorsal root ganglion injury named as emerging AAV toxicities at a 2026 workshop
Class context, onasemnogene abeparvovec (AAV9): boxed warning for serious liver injury and acute liver failure
Class context, delandistrogene moxeparvovec (AAVrh74): boxed warning for acute serious liver injury and acute liver failure
Class context, delandistrogene moxeparvovec (AAVrh74): two fatal cases of acute liver failure
Class context, delandistrogene moxeparvovec (AAVrh74): myocarditis warning and reduced ejection fraction
Class context, onasemnogene abeparvovec (AAV9): troponin elevation and cardiac findings in animals
Class context, systemic AAV: pooled incidence, timing, and outcome of myocarditis
Class context, systemic AAV: infection warnings in approved product labeling
Immunomodulation agents, sirolimus: boxed warning on immunosuppression and infection
Immunomodulation agents, rituximab: hepatitis B reactivation and serious infection warnings
Immunomodulation agents, eculizumab (C5 inhibitor used for impending complement activation): boxed warning for meningococcal infection
Immunomodulation agents, pegcetacoplan (C3 inhibitor used in cohort 3 only): boxed warning for infections with encapsulated bacteria
Immunomodulation agents, corticosteroids: myopathy in prednisone labeling
Class context, intravenous AAV9: dorsal root ganglion findings in animals and in clinical surveillance
Class context, onasemnogene abeparvovec (AAV9): vector integration and theoretical tumorigenicity
Special populations
Pediatric participants: age limits of each interventional trial
Pediatric participants: ages of those dosed in phase 1
Pediatric participants: dosing and immunomodulation in the phase 1 pediatric cohort
Pediatric participants: sequential safety run-in in the phase 2 trial
Pediatric participants: European paediatric investigation plan waiver for children under 3 years
Pediatric participants: studies and age groups in the European paediatric investigation plan
Pediatric participants: deferral and completion date of the European paediatric investigation plan
Children younger than 8 years: clinical data with RP-A501
No evidence found.
Pediatric participants: sirolimus labeling for children younger than 13 years
Adults older than 21 years at infusion
No evidence found.
Females: excluded from the interventional trials
Females: included in the natural history study
Females: planned study in the European paediatric investigation plan
Females: company statements on later indications, October 2026
Females: commentary on extending eligibility
Females: clinical data with RP-A501
No evidence found.
Males without hypertrophic cardiomyopathy: company statement on a later indication
Reduced ejection fraction and advanced heart failure: exclusion criteria
Reduced ejection fraction: exclusion added to the phase 1 protocol after the first heart transplantation
Reduced ejection fraction: outcome in the one participant enrolled with ejection fraction below 40%
Anti-AAV9 seropositive individuals: exclusion threshold in both interventional trials
Anti-AAV9 seropositive individuals: pre-existing immunity in the participant with thrombotic microangiopathy
Anti-AAV9 seropositive individuals: labeling of an approved AAV9 product
Individuals with a genetic predisposition to complement activation
Higher body weight: total vector dose in the participant with thrombotic microangiopathy
Prior heart transplant recipients and recipients of other organ transplants: excluded from both interventional trials
Prior heart transplant recipients: included in the retrospective cohort of the natural history study
Renal impairment: phase 1 eligibility criterion
Renal impairment: clinical data with RP-A501
No evidence found.
Hepatic impairment: phase 1 eligibility criteria
Hepatic impairment: labeling of approved systemic AAV products
Hematologic status: phase 1 eligibility criterion
History of thrombosis or thromboembolic events: exclusion criteria
Sirolimus hypersensitivity: phase 1 exclusion criterion
Pregnancy, lactation, and contraception requirements in the RP-A501 protocols
No evidence found.
Pregnancy and contraception: labeling of the immunomodulation agents and of an approved AAV9 product
Drug/Drug, drug/disease interactions
Effects of other drugs on RP-A501
Formal drug interaction studies of RP-A501
No evidence found.
Interaction between a C3 complement inhibitor and RP-A501 identified in the regulatory review
Proposed mechanism of the interaction between C3 inhibition and the vector
Identity of the C3 inhibitor in the registry record for the phase 2 trial
Effect of prophylactic immunomodulation on the antibody and complement response to the vector
Effect of corticosteroid compliance on myocardial transgene expression
Contraindication to sirolimus as an exclusion criterion
Vaccination required before administration
Effects of RP-A501 on other drugs
Effect of RP-A501 on the pharmacokinetics or exposure of other drugs
No evidence found.
Effect of RP-A501 on the dosing of concomitant immunomodulatory agents
Effect of RP-A501 on laboratory values that guide concomitant therapy
Dosing and administration
Dosage
Dose levels and cohorts in the phase 1 trial
Dose levels and cohorts in the phase 2 trial
Weight-based dosing and total administered dose in the first five phase 1 participants
| Participant | Weight | Cohort dose | Total dose |
|---|---|---|---|
| 1001 | “52.2 kg” | “6.7 x 10¹³ GC/kg” | “3.25 x 10¹⁵ GC” |
| 1002 | “89.1 kg” | “6.7 x 10¹³ GC/kg” | “5.97 x 10¹⁵ GC” |
| 1005 | “97.8 kg” | “6.7 x 10¹³ GC/kg” | “6.08 x 10¹⁵ GC” |
| 1006 | “82.7 kg” | “1.1 x 10¹⁴ GC/kg” | “9.10 x 10¹⁵ GC” |
| 1007 | “96.7 kg” | “1.1 x 10¹⁴ GC/kg” | “1.06 x 10¹⁶ GC” |
Highest dose permitted under the investigational new drug application
Discontinuation of the 1.1 × 10¹⁴ GC/kg dose, August 2021
Selection of 6.7 × 10¹³ GC/kg for the phase 2 trial
Rationale for the recalibrated 3.8 × 10¹³ GC/kg dose: relation to the phase 1 doses associated with efficacy
Rationale for the recalibrated dose: full capsid content of the current drug product
Rationale for the recalibrated dose: analytical characterization and nonclinical bridging
Product change underlying the recalibration: full-particle content of the in-house material
Maximum dose and treatment duration recorded in the European Union application
Administration
Route and number of administrations
Sequential administration with a minimum interval between participants
Pre-infusion requirements: antibody testing, baseline biopsy, and imaging
Care setting and duration of inpatient observation
Monitoring after infusion: laboratory and clinical surveillance schedule
Monitoring after infusion: complement activation and platelet count
Class context: laboratory surveillance recommended in the first 30 days after systemic AAV9 administration
Follow-up schedule after administration
Access and distribution
Expanded access: not offered
Current access through the pivotal trial: six recruiting sites in four countries
| Location | Quoted site name |
|---|---|
| La Jolla, California, United States | “University of California, San Diego” |
| Boston, Massachusetts, United States | “Boston Children's Hospital” |
| Philadelphia, Pennsylvania, United States | “Children's Hospital of Philadelphia” |
| Munich, Germany | “German Heart Center Munich” |
| Florence, Italy | “Meyer Children's Hospital” |
| London, United Kingdom | “Great Ormond Street Hospital & UCL Institute of Cardiovascular Science” |
Referral into the trial through the LAMPLIGHT study website
Commercial preparation stated for RP-A501 (October 2026)
Patient identification: activities the company lists on its path to launch (October 2026)
Patient identification: identified U.S. patients and diagnosis rate (data as of July 2026)
Sponsored genetic testing: Mission: Genome Danon Disease Program
Qualified Treatment Center model described for Kresladi, the company's approved gene therapy
Number, location, and qualification criteria of treatment centers for RP-A501
No evidence found.
Manufacturing and supply for commercialization
Regulatory filings outside the United States: intent stated in September 2024
European trial authorization and release of drug product for EU use
Timing of a marketing authorisation application in the European Union
No evidence found.
Co-prescribed/Concomitant therapies
Immunomodulation regimen by cohort and dose, as of October 2026
| Trial and cohort | Population and number dosed | Dose | Immunomodulatory regimen |
|---|---|---|---|
| Phase 1, cohort 1 | “Adult/Adolescent (n=3)” | “6.7 x 10¹³ GC/kg” | “Steroid (n=1); Steroid + Tacrolimus (n=2)” |
| Phase 1, cohort 2 | “Adult/Adolescent (n=2)” | “1.1 x 10¹⁴ GC/kg” | “Rituximab + Steroid + Tacrolimus” |
| Phase 1, cohort 1A | “Pediatric (n=2)” | “6.7 x 10¹³ GC/kg” | “Rituximab + Steroid + Sirolimus” |
| Phase 2, cohort 1 | “Adult/Adolescent (n=1)” | “6.7 x 10¹³ GC/kg” | “Rituximab + Steroid + Sirolimus” |
| Phase 2, cohort 2 | “Pediatric (n=3)” | “6.7 x 10¹³ GC/kg” | “Rituximab + Steroid + Sirolimus” |
| Phase 2, cohort 3 | “Adult/Adolescent and Pediatric with C3 inhibitor (n=2)” | “6.7 x 10¹³ GC/kg” | “Rituximab + Steroid + Sirolimus + C3 inhibitor” |
| Phase 2, cohort 4 | “Adult/Adolescent and Pediatric (n=12)” | “3.8 x 10¹³ GC/kg” | “Rituximab + Steroid + Sirolimus” |
Phase 1 regimen as administered, by cohort
Changes to the phase 1 regimen during the trial
Revision of the phase 2 regimen after the May 2025 events
Immunomodulatory and supportive medicines in the European Union application
| Agent | Form and route | Maximum daily dose | Maximum duration |
|---|---|---|---|
| Rituximab | “CONCENTRATE FOR SOLUTION FOR INFUSION Route of administration INTRAVENOUS INFUSION” | “750 mg/m2 milligram(s)/square meter” | “2 Week(s)” |
| Sirolimus | “COATED TABLET Route of administration ORAL USE” | “2 mg milligram(s)” | “3 Month(s)” |
| Prednisone | “TABLET Route of administration ORAL USE” | “60 mg milligram(s)” | “3 Month(s)” |
| Methylprednisolone sodium succinate | “POWDER FOR SOLUTION FOR INFUSION Route of administration INTRAVENOUS USE” | “0.8 mg/kg milligram(s)/kilogram” | “4 Week(s)” |
| Eculizumab | “SOLUTION FOR INFUSION Route of administration INTRAVENOUS INFUSION” | “1200 mg milligram(s)” | “3 Month(s)” |
| Paracetamol | “TABLET Route of administration ORAL USE” | “1 g gram(s)” | “2 Week(s)” |
| Diphenhydramine hydrochloride | “TABLET Route of administration ORAL USE” | “50 mg milligram(s)” | “2 Week(s)” |
Duration of immunosuppression after administration
Class context: immunosuppressive regimen recorded for the Danon disease program in a systematic review
Background cardiac therapy that participants continue
Implantable cardioverter-defibrillator use among treated participants
Effect of RP-A501 on quality measures
Product-specific effect on quality measures
No evidence found.
Quality measures specific to Danon disease or hypertrophic cardiomyopathy
No evidence found.
HEDIS Cardiac Rehabilitation (CRE): heart transplantation as a qualifying event
HEDIS Plan All-Cause Readmissions (PCR): definition
Medicare Part C Star Ratings: Plan All-Cause Readmissions (measure C18)
Medicare Part D Star Ratings: Medication Adherence for Hypertension (RAS antagonists) (measure D09) and its sacubitril/valsartan exclusion
CMS Hospital Readmissions Reduction Program: heart failure among the measured conditions
CMS Merit-based Incentive Payment System, Quality ID 005: renin-angiotensin system inhibitor therapy for heart failure with ejection fraction of 40% or less
CMS Merit-based Incentive Payment System, Quality ID 008: beta-blocker therapy for heart failure with ejection fraction of 40% or less
ACC/AHA heart failure performance measures: ejection fraction assessment and its heart transplant exclusion
ACC/AHA heart failure performance measures: counseling on implantable cardioverter-defibrillator implantation
ACC/AHA heart failure quality measures: patient-reported outcome questionnaires
ACC/AHA heart failure measures, 2024 update: new measures including counseling on contraception and pregnancy risks in cardiomyopathy
Heart transplant program performance metrics monitored by the Organ Procurement and Transplantation Network
Product comparison
Adeno-associated virus serotype 2i8 vector carrying the human LAMP2 isoform B transgene: European orphan designation, May 2025
| Field | Quoted record |
|---|---|
| Active substance | “adeno-associated viral vector serotype 2i8 containing the human LAMP2 isoform B transgene” |
| Intended use | “Treatment of Danon disease” |
| Orphan designation status | “Positive” |
| EU designation number | “EU/3/25/3062” |
| Date of designation | “22/05/2025” |
| Sponsor | “AskBio France” |
PPL-002 (Papillon Therapeutics): gene-modified hematopoietic stem and progenitor cells, FDA orphan drug designation announced October 2024
Hematopoietic stem cell approach: grant objective, candidate, and proposed mechanism
| Field | Quoted record |
|---|---|
| Grant number | “TRAN1-15230” |
| Institution | “University of California, San Diego” |
| Award value | “$5,180,389” |
| Translational candidate | “The candidate is CD34+ HSPCs transduced ex vivo with a LAMP2 lentiviral vector.” |
| Project objective | “Submission of Pre-IND materials” |
Hematopoietic stem cell approach: results in a mouse model presented in November 2025
Lipid nanoparticle LAMP2 messenger RNA: results in patient-derived cardiomyocytes presented in 2025
Company statement on gene therapy competitors, February 2026
Third-party descriptions of the development stage of RP-A501 relative to other approaches
Registered interventional trial of a product other than RP-A501 for Danon disease
No evidence found.
Heart transplantation as the current definitive treatment: company statements
Heart transplantation: company presentation of access and outcomes, October 2026
Heart transplantation in Danon disease: graft survival in 38 recipients from 8 centers
Heart transplantation and gene therapy in the international consensus statement
RP-A501 phase 1: survival and heart transplantation after infusion
Barriers to a controlled comparison of treatments in Danon disease
Direct or indirect comparison of RP-A501 with heart transplantation
No evidence found.
RP-A501 in the pivotal phase 2 trial: route, dose, immunomodulation, and antibody eligibility
Approved systemic AAV9 comparator: onasemnogene abeparvovec (Zolgensma) label attributes
Approved systemic AAV9 comparator: rebisufligene etisparvovec (Fayuvi) label attributes, approved September 2026
Approved systemic AAVrh74 comparator: delandistrogene moxeparvovec (Elevidys) label attributes
Approved systemic AAV5 comparator: etranacogene dezaparvovec (Hemgenix) label attributes
Published indirect comparison of RP-A501 with another gene therapy
No evidence found.
Place of product in therapy
Disease description
Definition and etiology
Definition: X-linked LAMP2 deficiency with cardiomyopathy, skeletal myopathy, and cognitive impairment
First description in 1981 and identification of primary LAMP-2 deficiency in 2000
LAMP2 gene: chromosomal location and exon structure
Three LAMP-2 isoforms and the isoforms affected by pathogenic variants
Variant types: proportion detected by sequence analysis and by deletion or duplication analysis
Variant types: counts of described LAMP2 germline variants by classification, 2026 review
Variant types: 68 variants in a 2014 literature and registry review
Variant types in Japanese families: 2018 nationwide survey and 2024 update
Genotype and phenotype: age at symptom onset by variant type
Genotype and phenotype: no confirmed correlation for loss-of-function variants; milder phenotypes with exon 9B and missense variants
De novo variants: reported share of cases
Germline and somatic mosaicism
Inheritance pattern and transmission risk
Recurrence risk when the variant is not detected in a parent
Penetrance by sex
Disease classification: from glycogen storage disease to a disorder of autophagy
Disease classification: grouping with glycogen storage disorders in cardiomyopathy guidelines
Disease classification: autophagic vacuolar myopathy
Outdated names for Danon disease
| Field | Quoted term |
|---|---|
| Outdated term | “X-linked vacuolar cardiomyopathy and myopathy” |
| Outdated term | “Glycogen storage disease IIb” |
| Outdated term | “X-Linked pseudoglycogenosis II” |
| Outdated term | “Antopol disease” |
| Outdated term | “Lysosomal glycogen storage disease without acid maltase deficiency” |
ICD-10-CM code E74.05: proposal presented in September 2022
| Proposed tabular modification | Quoted text |
|---|---|
| Subcategory | “E74.0 Glycogen Storage Disorders” |
| New code | “E74.05 Lysosome-associated membrane protein 2 [LAMP2] deficiency” |
| Inclusion term added | “Danon disease” |
ICD-10-CM code E74.05: effective October 1, 2023
OMIM entries for the disease and the gene
| Entry type | Quoted entry |
|---|---|
| Disease | “300257 DANON DISEASE” |
| Gene | “309060 LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 2; LAMP2” |
Orphanet entry: identifiers and classification
| Field | Quoted record |
|---|---|
| ORPHAcode | “ORPHA:34587” |
| Classification level | “Disorder” |
| Inheritance | “X-linked dominant” |
| Age of onset | “Childhood” |
| ICD-10 | “E74.0” |
| ICD-11 | “5C51.3” |
| OMIM | “300257” |
Epidemiology
Incidence of Danon disease
Incidence and birth prevalence in the general population
No evidence found.
Newborn screening and population screening series
No evidence found.
Nearest measure: share of Danon disease among children with hypertrophic cardiomyopathy
Nearest measure: timing of case identification in United States claims, health record, and laboratory data as of July 2026
Rising case detection with wider availability of LAMP2 testing
Prevalence of Danon disease
General population prevalence: stated as unknown in reference sources
Orphanet prevalence class and number of described families
Published cases: counts from literature reviews
Frequency in hypertrophic cardiomyopathy: range cited by the consensus statement and GeneReviews
Frequency in hypertrophic cardiomyopathy: under 1% in the 2022 expert consensus table of implicated genes
| Gene | Locus | Syndrome | Protein (functional effect) | Frequency | ClinGen classification |
|---|---|---|---|---|---|
| LAMP2 | “Xq24” | “Danon disease” | “Loss-of-function” | “<1%” | “Definite” |
Frequency in a French hypertrophic cardiomyopathy cohort: 2 of 197 index cases
Frequency in an unselected pediatric hypertrophic cardiomyopathy cohort, United States: 2 of 50 probands
Frequency in a pediatric cardiomyopathy cohort, China: 4 of 64 probands with hypertrophic cardiomyopathy
Frequency in hypertrophic cardiomyopathy with and without pre-excitation, United States: three series
Frequency in unexplained left ventricular hypertrophy with pre-excitation, China: 3 of 10 participants
Frequency in concentric left ventricular hypertrophy undergoing endomyocardial biopsy, China: 3 of 50 participants
Frequency in women under 40 years with advanced heart failure, Czech Republic: 12% of 60 participants
Frequency in a global cohort with unexplained increased left ventricular wall thickness: LAMP2 variants in 4 participants among 2,068 tested
| Gene | Male | Female | Total | % of participants with a pathogenic or likely pathogenic variant | Mean age (years) |
|---|---|---|---|---|---|
| LAMP2 | “1” | “3” | “4” | “0.9” | “26.75 ± 5.91” |
Frequency in a hypertrophic cardiomyopathy cohort, Türkiye: 392 participants, with 2 LAMP2 cases in the results and 1 in the discussion of the same article
Frequency in selected populations: range across studies
United States estimate extrapolated from hypertrophic cardiomyopathy prevalence: 10,000 to 25,000 cases in the 2022 code proposal
United States estimate from a hypertrophic cardiomyopathy-based model: method and stated limits, 2025 congress abstract
Estimates from literature, genomic databases, and health records: range of 240 to 11,807, 2026 congress abstract
Company estimate for the United States and Europe, Form 10-K filed February 2026: 15,000 to 30,000
Company modeled estimate, October 2026: 10,000 to 11,000 in the United States, including about 4,000 males
Company modeled estimate, October 2026: stated methods and data sources
Identified patients in the United States as of July 2026: more than 900
“Over 900 Identified US Danon Disease Patients” (opens the source at this quote in a new tab)
“Representing a current diagnosis rate under 10%” (opens the source at this quote in a new tab)
| Institutions | Share of identified patients |
|---|---|
| Top 25 | “30%” |
| Top 100 | “60%” |
| “All Institutions (n=290)” | “100%” |
Sponsored testing program page: approximately 15,000 in the United States, cited to company data on file
Japan: nationwide survey and later count of families
Diagnosed counts in registries
Sex distribution among diagnosed cases
Geographic and ancestry distribution
Natural history, survival, and mortality
Course by sex: consensus description
International Danon Disease Registry (116 participants, consent 2005 to 2022): cohort, age at diagnosis, and follow-up
International Danon Disease Registry: heart transplantation, ventricular assist device, and death by sex
| Outcome | Male participants: No. | Male participants: IQR or % | Female participants: No. | Female participants: IQR or % | Total: No. | Total: IQR or % |
|---|---|---|---|---|---|---|
| Heart failure outcome | “21” | “40.4” | “14” | “21.9” | “35” | “30.2” |
| Heart transplant | “17” | “32.7” | “13” | “20.3” | “30” | “25.9” |
| Left ventricular assist device | “2” | “3.8” | “2” | “3.1” | “4” | “3.4” |
| Death | “7” | “13.5” | “2” | “3.1” | “6” | “5.2” |
| Age at heart failure outcome, years | “19” | “16–23” | “26” | “14–39” | “20” | “16–27” |
International Danon Disease Registry: two age groups of heart failure outcome among females
International Danon Disease Registry: echocardiograms available for longitudinal analysis
Untreated males: first and last echocardiographic measurements by heart failure outcome
| Measurement | Examination | All males: median | All males: IQR | Heart failure outcome: median | Heart failure outcome: IQR | No heart failure outcome: median | No heart failure outcome: IQR |
|---|---|---|---|---|---|---|---|
| Left ventricular ejection fraction, % | First | “66” | “57–71” | “58” | “50–68” | “67” | “62–76” |
| Left ventricular ejection fraction, % | Last | “55” | “28–64” | “33” | “20–52” | “58” | “50–68” |
| Thickest left ventricular wall, cm | First | “1.2” | “0.9–1.9” | “1.7” | “1.2–2.4” | “1.1” | “0.8–1.5” |
| Thickest left ventricular wall, cm | Last | “1.5” | “1.0–2.5” | “1.9” | “1.6–2.5” | “1.4” | “1.0–2.3” |
| Left ventricular mass, g | First | “154” | “87–413” | “327” | “209–541” | “111” | “80–163” |
| Left ventricular mass, g | Last | “275” | “143–613” | “596” | “285–690” | “161” | “77–377” |
| Left ventricular end diastolic dimension, cm | First | “3.9” | “3.4–4.6” | “4” | “3.6–4.6” | “3.8” | “3.4–4.7” |
| Left ventricular end diastolic dimension, cm | Last | “4.4” | “3.7–5.3” | “6.3” | “4.8–6.6” | “4” | “3.7–4.7” |
Untreated females: first and last echocardiographic measurements by heart failure outcome
| Measurement | Examination | All females: median | All females: IQR | Heart failure outcome: median | Heart failure outcome: IQR | No heart failure outcome: median | No heart failure outcome: IQR |
|---|---|---|---|---|---|---|---|
| Left ventricular ejection fraction, % | First | “61” | “55–70” | “57” | “52–77” | “61” | “55–69” |
| Left ventricular ejection fraction, % | Last | “56” | “35–65” | “37” | “23–47” | “56” | “47–66” |
| Thickest left ventricular wall | First | “1.1” | “0.8–1.5” | “1.1” | “1.0–1.6” | “1.1” | “0.8–1.4” |
| Thickest left ventricular wall | Last | “1.2” | “1.0–1.7” | “1.2” | “0.9–2.0” | “1.2” | “1.0–1.7” |
| Left ventricular mass, g | First | “165” | “97–262” | “296” | “80–320” | “157” | “106–227” |
| Left ventricular mass, g | Last | “224” | “140–272” | “232” | “218–288” | “187” | “132–272” |
| Left ventricular end diastolic dimension | First | “4.3” | “3.6–4.9” | “4.4” | “2.8–5.2” | “4.3” | “3.9–4.8” |
| Left ventricular end diastolic dimension | Last | “4.7” | “4.1–5.8” | “5.9” | “5.5–6.4” | “4.5” | “4.0–5.3” |
Untreated males: change in echocardiographic parameters per year of age, by heart failure outcome
| Parameter | No heart failure outcome: participants (n) | No heart failure outcome: coefficient | No heart failure outcome: 95% CI | No heart failure outcome: P value | Heart failure outcome: participants (n) | Heart failure outcome: coefficient | Heart failure outcome: 95% CI | Heart failure outcome: P value |
|---|---|---|---|---|---|---|---|---|
| Left ventricular ejection fraction | “20” | “−0.888” | “−1.521 to −0.254” | “0.006” | “12” | “−2.461” | “−3.026 to −1.898” | “<0.001” |
| Left ventricular wall thickness | “23” | “0.101” | “0.069 to 0.133” | “<0.001” | “13” | “0.008” | “−0.036 to 0.051” | “0.734” |
| Left ventricular mass | “20” | “28.424” | “19.094 to 37.755” | “<0.001” | “13” | “34.183” | “20.548 to 47.817” | “<0.001” |
| Left ventricular end diastolic dimension | “22” | “0.123” | “0.082 to 0.162” | “<0.001” | “14” | “0.231” | “0.176 to 0.287” | “<0.001” |
Untreated females: change in echocardiographic parameters per year of age, by heart failure outcome
| Parameter | No heart failure outcome: participants (n) | No heart failure outcome: coefficient | No heart failure outcome: 95% CI | No heart failure outcome: P value | Heart failure outcome: participants (n) | Heart failure outcome: coefficient | Heart failure outcome: 95% CI | Heart failure outcome: P value |
|---|---|---|---|---|---|---|---|---|
| Left ventricular ejection fraction | “34” | “−0.832” | “−1.164 to −0.500” | “<0.001” | “9” | “−2.391” | “−3.477 to −1.305” | “<0.001” |
| Left ventricular wall thickness | “33” | “−0.012” | “−0.022 to −0.003” | “<0.009” | “9” | “−0.026” | “−0.0372 to −0.016” | “<0.001” |
| Left ventricular mass | “29” | “−0.631” | “−2.482 to 1.219” | “0.5037” | “9” | “1.868” | “−3.342 to 7.078” | “0.482” |
| Left ventricular end diastolic dimension | “31” | “0.05” | “0.031 to 0.069” | “<0.001” | “9” | “0.175” | “0.109 to 0.240” | “<0.001” |
Trajectories identified by sex and heart failure outcome
Echocardiographic parameters proposed as surrogate end points, registry limitations, and funding
International Danon Disease Registry, earlier analysis of 112 participants: ejection fraction, wall thickness, mass, and laboratory markers over time
Untreated males: annual increase in left ventricular mass and BNP, unpublished registry data shown by the sponsor in October 2026
Prospective study of nine males enrolled in 2019: cohort, censoring, and visit completion
Prospective study of nine males: echocardiographic change in pediatric participants over a mean of 24.5 months
| Parameter | At baseline (n = 8) | At last follow-up (n = 6) | Average paired difference |
|---|---|---|---|
| Left ventricular ejection fraction, % | “68.9 ± 4.8” | “64.3 ± 8.5” | “-5.9” |
| Maximum wall thickness, mm | “14.1 ± 6.7” | “15.6 ± 6.8” | “+ 3.4” |
| Left ventricular mass, g | “194.4 ± 131.1” | “200.7 ± 88.9” | “+ 64” |
| Left ventricular end-diastolic dimension, mm | “37.9 ± 5.7” | “36.5 ± 6.7” | “-0.5” |
| Global longitudinal strain, % | “-14.1 ± 2.9” | “-15.2 ± 4.2” | “+ 0.14” |
| Parameter | At baseline (n = 8) | At last follow-up (n = 6) |
|---|---|---|
| Maximum wall thickness z-score | “7.0 ± 6.0” | “9.4 ± 7.6” |
| Left ventricular mass z-score | “8.0 ± 6.2” | “11.0 ± 12.0” |
| Left ventricular end-diastolic dimension z-score | “-1.6 ± 1.8” | “-2.1 ± 1.5” |
Prospective study of nine males: NT-proBNP and high-sensitivity troponin T at baseline and follow-up
| Parameter | Mean, baseline (n = 9) | Mean, follow-up (n = 9) | Average paired difference | Normal range |
|---|---|---|---|---|
| NT-proBNP (pg/mL) | “932.2 ± 1055.9” | “1903.6 ± 1831.2” | “+ 971.3” | “< 125” |
| hs-cTnT (ng/L) | “41.1 ± 51.5” | “78.4 ± 51.2” | “+ 37.3” | “< 14” |
Registry of 82 participants from 36 families (2011): age at onset, diagnosis, transplant, and death by sex
Registry of 82 participants (2011): values printed in the population table
| Characteristic | Men (n=43) | Women (n=39) |
|---|---|---|
| Symptomatic clinical disease | “37 (94.9)” | “31 (91.2)” |
| Cardiac transplant | “13 (33.3)” | “6 (17.6)” |
| Living | “23 (59.0)” | “23 (67.6)” |
| Mean age at first symptom, years | “11.7” | “26.8” |
| Mean age at diagnosis, years | “13.1” | “30.9” |
| Mean age at cardiac transplant, years | “20.8” | “32.3” |
| Mean age at death, years | “20.1” | “40.2” |
Registry of 82 participants combined with 63 published cases: ages at events and proportion reaching transplant or death
Systematic review of 146 published cases through October 2017: composite of death, transplant, or ventricular assist device
European registry of 57 affected participants from 16 centers (2020): heart failure hospitalization, advanced therapies, and death
European registry, accepted manuscript: follow-up, age at death, deaths after transplant or assist device, and predictors of mortality
European registry, accepted manuscript: age of females at first heart failure hospitalization stated as 34 years in the body text
Spanish registry of 27 participants from 10 hospitals (2019): events and age at events by sex
| Event | Male participants (n=6) | Female participants (n=21) |
|---|---|---|
| Admission for heart failure | “2 (50)” | “10 (47)” |
| Age at first heart-failure episode, y | “23±16” | “37±9” |
| Heart transplant | “1 (20)” | “6 (30)” |
| Age at heart transplant, y (n=7) | “14” | “32±9” |
| Death | “3 (50)” | “3 (14)” |
| Age at death, y (n=6) | “23±13” | “40±14” |
| Death or heart transplant | “4 (57)” | “9 (43)” |
| Age at death or heart transplant (n=13) | “20±11” | “36±20” |
Japanese nationwide survey of 39 participants from 20 families (2018): age at onset, age at death, and cause of death
Seven young participants with LAMP2 cardiomyopathy diagnosed at ages 7 to 17 (2009): outcomes by age 24
Twenty males and 18 females from 13 families (2002): age at which each sex was affected
Age at symptom onset by sex and LAMP2 variant type: literature review through August 2013
Global registry of 33 participants (2019 abstract): age at symptom onset, diagnosis, and transplant by sex
Transplant recipients (38 participants from 8 centers): age at transplant by sex
Pediatric cohorts: transplant and death during follow-up
Predictor of outcome: global longitudinal strain
Predictor of outcome: Wolff-Parkinson-White pattern
Predictor of outcome: left ventricular mass and late gadolinium enhancement on cardiac magnetic resonance
Progression from a hypertrophic to a dilated phenotype in two females: rates of change
Literature survey of more than 500 reported cases (2020): prognosis in males
Pathophysiology
LAMP-2 protein: location and structure
Isoform functions: LAMP-2A in chaperone-mediated autophagy and LAMP-2B in heart, skeletal muscle, and brain
Impaired macroautophagy and failure of autophagosome and lysosome fusion
LAMP-2B in human cardiomyocytes: fusion mechanism in patient-derived cells
Autophagic vacuoles with sarcolemmal features in muscle
Glycogen accumulation
Mitochondrial dysfunction and impaired mitophagy
Oxidative stress and cardiomyocyte apoptosis
Metabolic profile of cardiac tissue and patient-derived cells
From hypertrophy to fibrosis, hypokinesis, and dilation
Conduction system involvement and pre-excitation: proposed mechanism
Pre-excitation: fasciculoventricular and extranodal pathways found at electrophysiological study
Pre-excitation: no accessory pathway at electrophysiological study in a 7-participant series
X-chromosome inactivation and variable expression in females
Mosaic distribution of LAMP-2 in the myocardium of females
Animal model: Lamp2 knockout mouse
Animal model: mouse carrying a human LAMP2 exon 6 deletion
Animal models: rat and zebrafish
Limits of animal and cell models and of current mechanistic understanding
Diagnosis
Formal diagnostic criteria: statements that none are established
Establishing the diagnosis by molecular genetic testing
Consensus diagnostic algorithm for clinical Danon disease
| Element | Quoted criterion |
|---|---|
| Genotype | “LAMP2 mutation (pathogenic or likely pathogenic)” |
| Clinical features required by sex | “Males: A or B or C; Females: A only” |
| A: cardiovascular | “Objective cardiovascular abnormality defined as any:” |
| A: left ventricular hypertrophy | “LVH: interventricular septal and posterior wall thickness age <18 y: z-score ≥2 age ≥18 y: ≥1.3 cm” |
| A: ejection fraction | “LVEF <50%” |
| A: electrocardiogram | “Electrocardiogram abnormalities: history of AF or AFL, VT, VF, or sudden cardiac death repolarization abnormalities, LVH/RVH, AV block pre-excitation pattern due to Wolff-Parkinson-White or fasciculoventricular pathways” |
| A: cardiac magnetic resonance | “Late gadolinium enhancement on cardiac MRI” |
| B: muscle | “Muscle abnormalities defined by any:”“Abnormal EMG, functional assessment (CPET, 6MWT), or timed tests”“Elevated CPK, AST, or ALT (>2 SD above the upper limit of normal)” |
| C: neurocognitive | “Intellectual disability, attention deficit disorder, or developmental delay” |
Consensus algorithm: variants of uncertain significance
Japanese diagnostic criteria: clinical features, muscle pathology, and LAMP-2 evaluation
Clinical suspicion: red flags in an individual with hypertrophic cardiomyopathy
Clinical suspicion: red flags in the 2023 ESC cardiomyopathy guideline
| Field | Quoted table text |
|---|---|
| Clinical red flags | “Short PR interval”“Massive LVH”“Skeletal myopathy”“Increased serum CK enzyme”“Intellectual disability”“X-linked inheritance” |
| Diagnosis | “NGS or target testing for LAMP-2 variants” |
| Specific cause | “Danon disease” |
Clinical suspicion: male adolescents with concentric hypertrophy, elevated enzymes, or pre-excitation
Electrocardiography: pre-excitation, short PR interval, and high voltage
Electrocardiography: frequency of pre-excitation differs across cohorts
Electrocardiography: features listed for Danon disease in the 2023 ESC cardiomyopathy guideline
Echocardiography: extreme concentric hypertrophy, outflow obstruction, and apical sparing strain
| Echocardiographic finding | Diseases listed |
|---|---|
| “Extreme concentric LVH (wall thickness ≥30 mm)” | “Danon disease, Pompe disease” |
Cardiac magnetic resonance: late gadolinium enhancement sparing the mid septum
Cardiac magnetic resonance: tissue characterization by sex in a 24-participant cohort
Laboratory findings: creatine kinase and transaminases
Muscle and endomyocardial biopsy: role in diagnosis
LAMP-2 immunostaining and western blot: results in males and in females
LAMP-2 protein assays in leukocytes by flow cytometry
Genetic testing: sequence analysis followed by deletion or duplication analysis
Genetic testing: variants that sequencing can miss
Genetic testing: pediatric and adult indications in the consensus statement
Guideline: LAMP2 testing in the 2024 AHA/ACC hypertrophic cardiomyopathy guideline
| Typical presentation age | Systemic features | Possible etiology | Diagnostic approach |
|---|---|---|---|
| “Youth and adolescence” | “Skeletal muscle weakness or movement disorder” | “Friedreich’s ataxia”“Danon disease”“Mitochondrial disease” | “Biochemical screening”“Neuromuscular assessment”“Genetic testing” |
Guidelines and statements: LAMP2 as a core gene in cardiomyopathy testing
Age at diagnosis
| Characteristic, prospective study of 9 male participants | Value |
|---|---|
| “Mean age at diagnosis, years” | “6.5 ± 5.2” |
Age at diagnosis among hypertrophic cardiomyopathy phenocopies in four European centres
Diagnostic delay: findings present before diagnosis
Misdiagnosis as sarcomeric hypertrophic cardiomyopathy
Underdiagnosis in females
Estimated diagnosis rate and genetic testing rates in cardiomyopathy, company presentation of October 2026
Differential diagnosis: selected genes and disorders
Differential diagnosis: PRKAG2-related disease
Differential diagnosis: Pompe disease
Differential diagnosis: Fabry disease
Differential diagnosis: sarcomeric hypertrophic cardiomyopathy and inheritance clues
Family cascade testing: consensus recommendations
Family cascade testing: GeneReviews and Orphanet
Screening of variant carriers without clinical findings
Evaluation at diagnosis: consensus recommendations
Diagnostic tests, typical findings, and surveillance intervals: consensus table
| Test | Typical findings | Frequency during follow-up care |
|---|---|---|
| Blood tests | “Raised NT-proBNP/troponin”“CK, AST, ALT, LDH” | “Yearly” |
| Electrocardiogram | “Pre-excitation, ventricular hypertrophy, extreme voltage, repolarization abnormalities, conduction disease” | “Yearly” |
| 24-hour Holter | “Atrial fibrillation, ventricular arrhythmias”“Atrioventricular block” | “Yearly”“Every 6 mo if enlarged atria” |
| Echocardiography | “Extreme hypertrophy”“25% LVOTO”“Apical sparing strain pattern” | “Yearly” |
| Cardiac magnetic resonance | “Extensive and diffuse LGE with midseptal sparing”“Increased T1 and ECV” | “Every 2-3 y” |
| Neurologic evaluation | “Proximal muscle weakness” | “Yearly if symptoms, otherwise, every 3-4 y” |
| Development evaluation | “Intellectual disability” | “At baseline and if new manifestations appear” |
| Ophthalmologic evaluation | “Cone-rod dystrophy”“Peripheral pigmentation” | “Every 3-5 y” |
| Genetic counseling | “Cascade screening”“Family planning” | “At diagnosis and when needed” |
Evaluations following initial diagnosis: GeneReviews
Recommended cardiac surveillance: GeneReviews
Status of practice guidelines and funding of the consensus statement
Clinical presentation - signs and symptoms
Multisystem presentation by sex: classic triad in males and isolated cardiac disease in females
Reported clinical characteristics by sex in a registry of 82 participants (percentage of those with data)
| Characteristic | Men (n=26) | Women (n=18) |
|---|---|---|
| Symptomatic heart disease | “88.5” | “77.7” |
| Chest pain | “41.6” | “37.5” |
| Palpitations | “76.5” | “68.8” |
| Hypertrophic cardiomyopathy | “88” | “33.3” |
| Dilated cardiomyopathy | “12” | “27.7” |
| Conduction abnormality | “86.4” | “80” |
| Wolff-Parkinson-White | “68.2” | “26.7” |
| Cardiac ablation | “53.3” | “30.8” |
| Defibrillator implantation | “41.2” | “31.3” |
| Learning and cognitive problems | “100” | “46.6” |
| Visual and retinal abnormalities | “69.2” | “64.2” |
| Symptomatic muscle disease | “80” | “50” |
| Muscle cramping | “9.1” | “15.3” |
| Neuropathy | “9.1” | “38.5” |
| Symptomatic respiratory disease | “50” | “16.7” |
| Symptomatic gastrointestinal disease | “76.5” | “50” |
Earliest manifestations in children
Cardiac: hypertrophic and dilated phenotypes by sex
Cardiac: magnitude of left ventricular hypertrophy
Cardiac: symptoms
Cardiac: pre-excitation and Wolff-Parkinson-White pattern, frequency across cohorts
Cardiac: electrophysiology studies of the pre-excitation pattern
Cardiac: atrial and ventricular arrhythmias
Cardiac: conduction disease
Cardiac: sudden cardiac death and cardiac arrest
Cardiac: natriuretic peptide and troponin elevation
Skeletal muscle: frequency and distribution of weakness
Skeletal muscle: quantitative strength and timed function tests
Skeletal muscle: creatine kinase
Skeletal muscle and hepatic laboratory values in nine males at baseline and follow-up
| Parameter | Mean, baseline (n = 9) | Mean, follow-up (n = 9) | Normal range |
|---|---|---|---|
| CPK (U/L) | “1393.8 ± 831.0” | “1340.9 ± 794.5” | “39–308” |
| Aldolase (units/L) | “21.9 ± 7.7” | “21.4 ± 9.0” | “1.0–7.5” |
| AST (U/L) | “407.0 ± 175.2” | “361.9 ± 177.2” | “0–40” |
| ALT (U/L) | “259.7 ± 110.6” | “301.3 ± 134.3” | “0–41” |
| LDH (U/L) | “1069.3 ± 346.1” | “1223.3 ± 565.0” | “140–280” |
Neurocognitive: intellectual disability and learning difficulty by sex
Neurocognitive: standardized testing in pediatric males
Neurocognitive: intelligence testing in 13 adolescents and adults of both sexes
Psychiatric: mood, anxiety, attention-deficit, and autism spectrum diagnoses
Ophthalmic: retinopathy and visual acuity
Hepatic: transaminase elevation and hepatomegaly
Gastrointestinal and respiratory symptoms
Exercise capacity: peak oxygen uptake in pediatric males
Long-term morbidity
Progression to systolic dysfunction and end-stage heart failure
Myocardial fibrosis on cardiac magnetic resonance
Implanted cardiac devices and catheter ablation: frequency in cohorts
Stroke and thromboembolism
Skeletal myopathy: course over time and ambulation
Retinal disease: change with age
Cognitive impairment: course over time
After heart transplantation: skeletal muscle weakness and other extracardiac events
Burden of Danon disease
Humanistic burden and health-related quality of life
Instruments used in the prospective study of nine males
Pediatric Cardiac Quality of Life Inventory: patient-reported scores
Pediatric Cardiac Quality of Life Inventory: parent-reported scores
Pediatric quality of life questionnaire: child and parent scores at baseline and last follow-up
| Scale (maximum 100) | Child: baseline (n = 7) | Child: last follow-up (n = 5) | Parent: baseline (n = 8) | Parent: last follow-up (n = 6) |
|---|---|---|---|---|
| Physical functioning | “50.0 ± 6.3” | “44.8 ± 6.3” | “47.1 ± 8.4” | “36.5 ± 8.4” |
| Emotional functioning | “66.7 ± 24.8” | “75.0 ± 24.8” | “52.9 ± 30.4” | “64.3 ± 30.4” |
| Social functioning | “54.2 ± 32.9” | “70.0 ± 32.9” | “44.6 ± 13.7” | “52.1 ± 13.7” |
| School functioning | “45.8 ± 30.1” | “47.5 ± 30.1” | “33.6 ± 9.4” | “45.2 ± 9.4” |
| Psychosocial health summary | “55.3 ± 24.7” | “64.2 ± 24.7” | “43.7 ± 16.0” | “53.9 ± 16.0” |
| Physical health summary | “50.0 ± 6.3” | “44.8 ± 6.3” | “47.1 ± 8.4” | “36.5 ± 8.4” |
| Total | “53.4 ± 17.6” | “57.4 ± 17.6” | “44.9 ± 8.6” | “47.9 ± 8.6” |
Scores in relation to healthy children and children with other chronic conditions
Validation status of quality-of-life instruments in Danon disease
Kansas City Cardiomyopathy Questionnaire and PedsQL scores by device status and functional class
Functional class in untreated cohorts
Schooling, employment, and independence
“For school functioning, baseline mean was 33.6 ± 9.4” (opens the source at this quote in a new tab)
Externally led patient-focused drug development meeting on genetic cardiomyopathies (2026)
Voice of the Patient report for Danon disease
No evidence found.
Health state utility values in Danon disease
No evidence found.
Economic burden and healthcare resource utilization
Cost of illness or healthcare resource utilization study specific to Danon disease
No evidence found.
Danon disease: heart failure outcomes and cardiac device implantation in 116 registry participants
| Measure | Male, No. | Male, % | Female, No. | Female, % | Total, No. | Total, % |
|---|---|---|---|---|---|---|
| Participants | “52” | “44.8” | “64” | “55.2” | “116” | |
| Heart failure outcome | “21” | “40.4” | “14” | “21.9” | “35” | “30.2” |
| Heart transplantation | “17” | “32.7” | “13” | “20.3” | “30” | “25.9” |
| Left ventricular assist device | “2” | “3.8” | “2” | “3.1” | “4” | “3.4” |
| Cardiovascular implantable electronic device | “19” | “36.5” | “26” | “40.6” | “45” | “38.8” |
| Pacemaker | “2” | “3.8” | “0” | “0.0” | “2” | “1.7” |
| Automatic implantable cardioverter defibrillator | “17” | “32.7” | “26” | “40.6” | “43” | “37.1” |
Danon disease: age at heart failure outcome by sex
Danon disease: age at first heart failure hospitalization and use of transplantation or assist devices in a European registry
Danon disease: average ages at first symptom, heart transplantation, and death
Danon disease: composite of death, heart transplantation, or ventricular assist device in published cases
Danon disease: age and ventricular function at heart transplantation in 38 recipients
Heart transplantation in the United States, all diagnoses: estimated 2025 billed charges by component of care
| Component of care | Estimated billed charges per heart transplant, United States dollars |
|---|---|
| 30 days pretransplant | “67,000” |
| Procurement | “214,500” |
| Hospital transplant admission | “1,220,400” |
| Physician during transplant admission | “105,200” |
| 180 days posttransplant discharge | “277,400” |
| Outpatient immunosuppressants and other drugs | “34,200” |
| Total | “1,918,700” |
Heart transplantation in the United States, all diagnoses: estimated 2025 volume, utilization, and length of stay
Pediatric heart transplant recipients, all diagnoses: hospitalization costs, 2002 to 2016
Pediatric heart transplant hospitalizations, all diagnoses: hospital charges, 1997 to 2006
Children bridged to heart transplantation with mechanical circulatory support, all diagnoses: hospitalization costs
Adults receiving a left ventricular assist device in the United States, all diagnoses: hospitalization cost and national expenditure
Pediatric heart failure-related hospitalizations in the United States, all diagnoses: volume, length of stay, and charges
Adult heart failure hospitalizations in the United States, all diagnoses: cost per hospitalization and annual medical cost
Implantable cardioverter-defibrillator placement admissions in United States adults with and without congenital heart disease: hospital charges
Adults with obstructive hypertrophic cardiomyopathy in United States commercial and Medicare supplemental claims: annual resource use and cost
Economic impact of Danon disease on families
More than one affected member per family
Caregivers who are themselves affected: demands named by a patient organization
Costs to families named by a patient organization
Geographic dispersion of families and travel to specialized centers
Waiting for transplantation: family statements shown in a sponsor presentation (October 2026) and published reports
Caregiver time, work loss, and out-of-pocket cost: published studies
No evidence found.
Economic impact of diagnostic testing
Genetic testing as the confirmatory diagnostic test
Test content: LAMP2 sequencing with deletion and duplication analysis, alone or within a cardiomyopathy panel
Tissue-based LAMP-2 protein assays: availability
Genetic confirmation as a trial eligibility requirement
Sponsored no-charge genetic testing and counseling program for suspected Danon disease
Population figure stated on the sponsored testing program page
Commercial cardiomyopathy panel that includes Danon disease: size and billing
Genetic testing rates in cardiomyopathy and identified United States patients: company presentation, October 2026
Diagnostic yield of no-charge sponsored cardiomyopathy and arrhythmia panel testing in 4782 participants
Cost-effectiveness of genetic testing in families with hypertrophic or dilated cardiomyopathy: Australian models
Commercial payer coverage criteria for cardiomyopathy gene panels, effective September 2026
Procedure code for hereditary cardiomyopathy panel sequencing
Florida Medicaid independent laboratory fee schedule, January 2026: rate for code 81439
| Procedure code | Fee schedule amount as printed |
|---|---|
| 81439 | “392.06” |
Medicare Clinical Laboratory Fee Schedule payment rate for LAMP2 or cardiomyopathy panel testing
No evidence found.
Anti-AAV9 antibody testing as an eligibility test
Published cost of anti-AAV9 antibody testing
No evidence found.
Endomyocardial biopsy as the expression assessment in the pivotal trial
Endomyocardial biopsy in United States heart transplant recipients: paid amounts and complications in claims data, 2016 to 2019
Approaches to treatment
Current treatment options and standard of care
Implantable cardioverter-defibrillators
Basis of management recommendations: expert opinion and extrapolation from hypertrophic cardiomyopathy guidelines
Consensus statement: low threshold for defibrillator implantation; risk models not validated in Danon disease
Consensus statement: subcutaneous device and defibrillation threshold testing
Consensus statement: activity restriction with and without a defibrillator
Italian Society of Cardiology position paper: defibrillator recommendation that names Danon disease
GeneReviews: timely consideration of a defibrillator
Earlier management proposal: clinical features that prompt defibrillator therapy
AHA/ACC hypertrophic cardiomyopathy guideline: Danon cardiomyopathy outside the guideline's scope
ESC cardiomyopathy guideline: insufficient data on sudden death risk factors in Danon disease
Device use in the International Danon Disease Registry: 116 participants
Device use and indications in a European registry: 57 participants
Appropriate device interventions in the European registry
Appropriate shocks in a multicenter cohort with pre-excitation: 13 participants
Appropriate shocks in a single-center series: 10 participants
Sustained ventricular arrhythmia in a three-family series: 7 participants
Failure of defibrillation: one death among 7 participants
Transvenous device unable to defibrillate and subcutaneous device effective: single case
Age at defibrillator implantation and frequency across published cohorts
Arrhythmia management
Consensus statement: electrophysiological study and ablation for pre-excitation
Consensus statement: rhythm monitoring for atrial fibrillation and atrioventricular block
Pacemaker implantation for heart block or sinus node dysfunction
Italian Society of Cardiology position paper: ablation recommendation that names Danon disease
GeneReviews: electrophysiologic study, ablation, and reduced ablation efficacy
Ablation outcomes and repeat procedures in a United States registry
Frequency of arrhythmias and ablation procedures in males
Frequency of ablation procedures and defibrillator implantation in females
Electrophysiological study findings with pre-excitation: fasciculoventricular and extranodal pathways in a multicenter cohort
Electrophysiological study findings with pre-excitation: fasciculoventricular pathways in two smaller series
Electrophysiological study findings: accessory pathway excluded in all 4 males of a three-family series
Atrial fibrillation and thromboembolic stroke
Consensus statement: embolic stroke from intracardiac thrombus
Anticoagulation: hypertrophic cardiomyopathy guideline text that does not name Danon disease
Anticoagulation after left ventricular apical thrombus and stroke: single case
Catheter ablation of atrial fibrillation: single case
Heart failure medical therapy
Consensus statement: no disease-specific therapy; symptom-guided heart failure and antiarrhythmic medication
Consensus statement: renin-angiotensin-aldosterone system inhibition and beta blockers without proof of efficacy
Consensus statement: benefit of guideline-directed medical therapy unknown
Consensus statement: expected tolerance and agents to avoid
GeneReviews: standard heart failure treatment with careful volume management; benefit of neurohormonal therapy not established
Earlier management proposal: standard heart failure approaches
ESC cardiomyopathy guideline: no approved etiological therapy
Company statement on heart failure medications and disease progression
Atrioventricular block and rate-slowing medication in affected women
Therapies to attenuate fibrosis: registry authors' statement
Controlled trials of heart failure drugs in Danon disease
No evidence found.
Mechanical circulatory support
GeneReviews: caution with durable support because of biventricular involvement
AHA/ACC/HFSA heart failure guideline: anatomic criteria for durable support, in text that does not name Danon disease
AHA/ACC hypertrophic cardiomyopathy guideline: limited data on circulatory support, in text that does not name Danon disease
Frequency of left ventricular assist device use in a Japanese nationwide survey
| Group | Left ventricular assist device |
|---|---|
| Males | “1/17 (6%)” |
| Females | “4/22 (18%)” |
Donor shortage and bridging in Japan
First reported left ventricular assist device implantations: two cases
Bridge to transplantation in an adult male: single case
Biventricular support for 791 days in a 12-year-old girl: single case
Bridge to transplantation for 34 days in an adolescent: one of two brothers
Death with a left ventricular assist device in the European registry: single participant
Heart transplantation
Consensus statement: indication and outcome
Consensus statement: immunosuppression considerations after transplantation
Italian Society of Cardiology position paper: transplantation recommendation that names Danon disease
GeneReviews: timely consideration of transplantation
AHA/ACC hypertrophic cardiomyopathy guideline: referral with preserved ejection fraction, in text that does not name Danon disease
Multicenter transplant cohort: 38 recipients from 8 centers
Multicenter transplant cohort: age and ejection fraction at transplantation
Multicenter transplant cohort: deaths, retransplantation, and 5-year graft survival
Age at transplantation in females: two age groups in an unpublished subanalysis
Average age at transplantation in a pooled case series
European registry: deaths within one year in male recipients of a transplant or assist device
European registry: authors' comments on transplantation in males
Single-center long-term follow-up: 4 recipients
Transplantation in three small center or family series
Transplantation in Japan: one recipient among 39 participants
Skeletal muscle weakness after transplantation and corticosteroid withdrawal: two cases
Late weakness after transplantation that led to the diagnosis: single case
Cardiac allograft vasculopathy and retransplantation: single case
Fatal thrombotic microangiopathy after pediatric transplantation: single case
Psychiatric and cognitive decline 15 years after transplantation: single case
Rehabilitation after transplantation
United States benchmark: survival after heart transplantation for any diagnosis
Multidisciplinary supportive care
Consensus statement: multidisciplinary care at referral centers
Physical therapy for skeletal myopathy
Rehabilitation strategy suggested by muscle activation testing
Developmental assessment and educational support
Psychiatric assessment
Neuropsychological evaluation across the life span: single case
Ophthalmic surveillance and low vision support
Ophthalmic findings in a systematic review of 70 patients
Genetic counseling and family planning
Social work and care coordination
Physical activity guidance
Limitations of current therapies
Summary
No approved therapy corrects the LAMP2 deficiency that causes Danon disease. The 2023 international consensus statement states that there are “no available therapies to specifically treat Danon disease”, that management rests on expert opinion and extrapolation from hypertrophic cardiomyopathy guidelines, and that no proof of efficacy exists for renin-angiotensin-aldosterone system inhibition or beta blockers in this disease. The sudden death risk models developed for hypertrophic cardiomyopathy have not been validated in Danon disease. Device therapy has documented failures: in a series of 7 participants, 1 died at age 12 from ventricular fibrillation that repeated defibrillator shocks did not terminate. GeneReviews advises caution with durable mechanical circulatory support because the disease involves both ventricles and states that ablation efficacy may be decreased.
Heart transplantation is the one intervention that sources credit with a survival benefit, and a minority of patients receive it: 30 of 116 participants (25.9%) in the International Danon Disease Registry, and 17.6% in a figure cited by a 2024 review. In a cohort of 38 recipients from 8 centers, the median age at transplantation was 20.2 years, 2 recipients died, 2 underwent retransplantation, estimated 5-year graft survival was 87.1% (95% CI 63.6% to 95.9%), and 7 episodes (19%) of grade 2 or 3 acute cellular rejection were reported. In a European registry, 5 of 8 male recipients of a transplant or an assist device (62%) died within 1 year of the procedure. In the OPTN/SRTR 2023 annual data report for the United States, pediatric waitlist mortality was 11.7 deaths per 100 patient-years, and 62 of the 733 pediatric candidates removed from the waiting list in 2023 (8.5%) died. Case reports after transplantation describe corticosteroid-associated skeletal muscle weakness, allograft vasculopathy that required retransplantation, and fatal thrombotic microangiopathy. The company developing RP-A501 describes transplantation as “not curative of the disorder in the long-term”, and registry authors advise transplant clinics to prepare for neuromuscular and psychiatric complications in the peri- and postoperative period.
No disease-modifying therapy
Transplantation as the only therapy with a survival benefit
Share of patients who receive a transplant
Donor organ availability and waitlist outcomes: United States pediatric candidates for any diagnosis
Waiting time in Danon disease case reports
Survival and early mortality after transplantation: two cohorts with different results
Morbidity after transplantation and lifelong immunosuppression
Device limitations
Disease outside the heart after cardiac treatment
Place in treatment, anticipated use, and care setting
Summary
RP-A501 is investigational and has no established place in therapy. The pivotal phase 2 trial enrolls males aged 8 years or older with a pathogenic or likely pathogenic LAMP2 variant, left ventricular hypertrophy with an ejection fraction of 50% or more, New York Heart Association class II to III symptoms, and elevated high-sensitivity troponin I. It excludes anti-AAV9 neutralizing antibody titers above 1:40, severe heart failure requiring advanced therapies, and prior transplantation. The studied population therefore has disease earlier than the end stage at which heart transplantation is used. Reduced ejection fraction was excluded after the 1 phase 1 participant with baseline systolic dysfunction progressed to transplantation 5 months after infusion. The company states that its initial focus is males with symptomatic hypertrophic cardiomyopathy and presents females and males before cardiomyopathy onset as potential later expansions that would need additional clinical evidence and regulatory approval.
The trial care setting is a specialized center. The registry lists 6 recruiting locations in 4 countries, participants are hospitalized for infusion and safety monitoring, the first 3 participants treated at the recalibrated dose were discharged 1 to 2 weeks after infusion, and site follow-up continues for 5 years. Treatment involves endomyocardial biopsy, which supplies one of the two co-primary endpoint criteria, and an immunomodulatory regimen of rituximab, sirolimus, and corticosteroids that the company states is discontinued 2 to 3 months after infusion. Before a launch that the company projects for mid-2029, its stated plans include genetic testing of young people with hypertrophic cardiomyopathy, cascade testing of relatives, and relationships with treatment centers; it reports more than 900 identified patients in the United States and a diagnosis rate under 10%. In a survey of 123 cardiology providers, 85% had never referred a patient to a gene therapy trial and 51% recognized the need for immunosuppression expertise.
Population studied in the pivotal trial: males with hypertrophy and preserved ejection fraction
Exclusion of advanced heart failure, prior transplantation, and anti-AAV9 antibodies
Exclusion of reduced ejection fraction after the phase 1 experience
Company statement of initial focus and potential later populations, October 2026
Company positioning relative to heart transplantation
Care setting in the trials: hospitalization for infusion and site follow-up for 5 years
Length of stay in the first 3 participants treated at the recalibrated dose
Number of trial locations
Immunomodulation given with the infusion and its duration
Endomyocardial biopsy before and after treatment
Expert commentary: eligibility of females and treatment burden
Consensus statement: patient selection for gene therapy
Review statement on current treatment and the phase of gene therapy studies
Company statements on patient identification, October 2026
Company statements on treatment centers and trial sites, October 2026
Cardiology provider readiness for cardiac gene therapy: survey of 123 providers
Heterogeneity of treatment effect
Evidence base: individual-level description without statistical testing
Sex: all treated participants are male
Sex: barriers to a trial in females
Baseline ejection fraction: single phase 1 participant with systolic dysfunction who progressed to transplantation
Later transplantation in a pediatric low-dose participant: single observation after the July 2026 data cut
Age and dose cohort: left ventricular mass index change by phase 1 participant at the most recent visit (36 to 84 months), data extracted July 31, 2026
| Cohort | Participant | Change in left ventricular mass index, baseline to most recent visit (g/m2.7) |
|---|---|---|
| Low dose, adult or adolescent | 1 | “-32%, 85.0 to 57.8” |
| Low dose, adult or adolescent | 2 | “-31%, 260.2 to 178.9” |
| Low dose, adult or adolescent | 3 | “-12%, 98.2 to 86.7” |
| High dose, adult or adolescent | 4 | “-7%, 68.6 to 63.6” |
| Low dose, pediatric | 6 | “-47%, 141.5 to 74.7” |
| Low dose, pediatric | 7 | “+3%, 82.0 to 84.9” |
Original-dose phase 2 cohorts: response in 3 of 4 participants
Dose level: high dose discontinued after thrombotic microangiopathy in 1 of 2 participants
Dose level: outcomes at the recalibrated dose not yet known
Immunomodulatory regimen: serious adverse events in both participants given a C3 inhibitor
Skeletal myopathy: corticosteroid-related exacerbation in 3 of 7 phase 1 participants
Anti-AAV9 antibody status: participants with pre-existing antibodies not treated
Genotype: variant class and phenotype severity
Treatment response by LAMP2 variant type
No evidence found.
Care management intervention strategies
Eligibility assessment: baseline testing at the study site
Eligibility assessment: anti-AAV9 antibody testing
Eligibility assessment: three-month biomarker run-in before treatment, as stated in August 2025
Immunomodulation: regimen under the modified protocol
Immunomodulation: changes made during phase 1 to limit steroid myopathy and renal toxicity
Infection prophylaxis regimen during immunomodulation
No evidence found.
Complement monitoring and threshold for a C5 inhibitor
Platelet and terminal complement complex monitoring for 3 months in the first 3 participants at the recalibrated dose
Timing of immune adverse events after AAV gene therapy: meta-analysis across diseases
Cardiac and extracardiac surveillance schedule in the consensus statement
| Test | Frequency during follow-up care |
|---|---|
| Blood tests | “Yearly” |
| 24-hour Holter monitoring | “Every 6 mo if enlarged atria” |
| Cardiac magnetic resonance | “Every 2-3 y” |
| Neurologic evaluation | “Yearly if symptoms, otherwise, every 3-4 y” |
| Development evaluation | “At baseline and if new manifestations appear” |
| Ophthalmologic evaluation | “Every 3-5 y” |
| Genetic counseling | “At diagnosis and when needed” |
Surveillance schedule in GeneReviews
| Evaluation | Frequency |
|---|---|
| Electrocardiography | “At least annually” |
| Echocardiography | “At least every 1-2 yrs, transitioning to every 6 mos once hypertrophy becomes moderate or if hypertrophy is rapidly progressive” |
| Cardiac MRI | “Consider every 1-2 yrs to evaluate progression of fibrosis.” |
| Ambulatory arrhythmia monitoring | “As needed for eval of symptoms consistent w/bypass track (e.g. palpitations, pre-syncope)” |
| Formal developmental assessments | “Every 3-5 yrs during childhood” |
| Ophthalmologic examination | “Every 3-5 yrs or as needed based on concerns about visual acuity, visual field deficits, &/or color vision (as an indicator of cone function)” |
Surveillance of genotype-positive relatives without cardiomyopathy
Family cascade testing
Company-sponsored genetic testing program: eligibility and family variant testing
Transition planning and educational support
Patient and caregiver experience of gene therapy administration
Long-term follow-up in the RP-A501 studies
FDA guidance: duration of long-term follow-up by product type
FDA guidance: yearly examinations and registries after gene therapy
Natural history study and registry
Other product development or post-marketing obligations required by the FDA
EMA paediatric investigation plan: agreed clinical studies
EMA paediatric investigation plan: deferral granted and completion by December 2034
EMA paediatric investigation plan: compliance check status
| Field | Quoted record |
|---|---|
| Compliance check done | “No” |
Evidence after accelerated approval: company statements on full approval and confirmatory trials
Post-marketing requirements or commitments issued by the FDA for RP-A501
Not applicable.
Ongoing post-approval monitoring
FDA guidance on long-term follow-up after gene therapy: duration recommended for AAV vectors
Long-term follow-up after gene therapy: company statement on FDA guidance
Follow-up planned in the pivotal phase 2 trial: 5 years after administration
Long-term follow-up of phase 1 participants: registry record states 2 to 5 additional years
Long-term follow-up of phase 1 participants: October 2026 presentation states up to 10 years
EMA paediatric investigation plan: long-term safety and efficacy concerns for paediatric use
Post-approval monitoring requirements for RP-A501 (registry, risk evaluation and mitigation strategy, or labeling)
Not applicable.