Evicenter
P&T meetings

RP-A501 (AAV9.LAMP2B)

Danon disease

Regulatory submission
BLA planned for late 2028
Last updated
300 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Mechanism of action

9 evidence topics · 16 sources

Product composition: AAV9 capsid carrying a full-length wild-type human LAMP2B transgene

“RP-A501 is our investigational gene therapy for the treatment of DD and consists of a recombinant adeno-associated serotype 9 (AAV9) capsid containing a full-length, wild-type version of the human LAMP2B transgene which is administered as a single intravenous (IV) infusion.” (opens the source at this quote in a new tab)

“RP-A501 is a gene therapy product consisting of an rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single IV infusion.” (opens the source at this quote in a new tab)

“Active substance Adeno-Associated Virus Serotype 9 Vector Containing the Human LAMP2 Isoform B Transgene” (opens the source at this quote in a new tab)

Intended effect: restoration of LAMP2B protein expression and repair of autophagy

“Goal • Restore LAMP2B protein expression • Repair autophagy • Normalize myocardial structure & function” (opens the source at this quote in a new tab)

“LAMP2 Gene Addition: Restores Cellular Recycling” (opens the source at this quote in a new tab)

“AAV9 with functional LAMP2B coding sequence Gene addition to cardiomyocytes” (opens the source at this quote in a new tab)

“LAMP2B restored on lysosome membrane Autolysosome fusion restored” (opens the source at this quote in a new tab)

“RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid containing a functional version of the human LAMP2B transgene (AAV9.LAMP2B) which is administered as a single intravenous (IV) infusion.” (opens the source at this quote in a new tab)

“In clinical studies, RP-A501 has been shown to target cardiac cells (cardiomyocytes) and deliver the functional LAMP2B gene to heart tissue, which led to improved cardiac structure and function in patients.” (opens the source at this quote in a new tab)

Autophagic defect the product is designed to correct

“LAMP-2b is essential for autophagosome-lysosome fusion, a critical step in macroautophagy. Thus, LAMP-2b deficit leads to impaired autophagic flux, intracellular vacuolization, and progressive cellular dysfunction and death[5,6].” (opens the source at this quote in a new tab)

“This mutation results in accumulation of autophagosomes and glycogen, particularly in cardiac muscle and other tissues, which ultimately leads to heart failure, and for male patients, frequent death during adolescence or early adulthood.” (opens the source at this quote in a new tab)

Rationale for the AAV9 capsid: cardiac tropism

“AAV9: demonstrated myocardial tropism” (opens the source at this quote in a new tab)

“AAV9 demonstrates tropism to: • Cardiomyocytes • Skeletal muscle • Liver • Brain tissue” (opens the source at this quote in a new tab)

“AAV9 Vector Shows Consistent & Strong Cardiac Tropism In Several Studies Across Different Species” (opens the source at this quote in a new tab)

“AAV serotype 9 (AAV9) has been shown to be highly efficient at delivering genes to major tissues including the liver, heart, skeletal muscle, and central nervous system (16–20), all affected organs, and tissues in DD.” (opens the source at this quote in a new tab)

Rationale for the B isoform: predominant LAMP2 isoform in cardiomyocytes

“LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes.” (opens the source at this quote in a new tab)

“Because cardiac disease is severe in patients with DD and several patients have been identified with mutations in the exon specifically encoding LAMP2B, this isoform has been postulated to be critical in the pathogenesis of the disease (11, 12).” (opens the source at this quote in a new tab)

“As stated above, we specifically tested the LAMP2B isoform because human genetic studies indicate that isolated LAMP2B mutations are sufficient to cause disease, whereas no patients have been identified with deficiencies isolated in LAMP2A or LAMP2C.” (opens the source at this quote in a new tab)

“Alternative splicing in exon 9 generates 3 isoforms: LAMP-2a, LAMP-2b, and LAMP-2c. LAMP-2b is mainly expressed in cardiac, skeletal muscle and in the central nervous system and its deficiency determines the disease development[2].” (opens the source at this quote in a new tab)

Rationale for the B isoform: requirement for autophagosome-lysosome fusion in human cardiomyocytes

“Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome–lysosome fusion in human cardiomyocytes (CMs).” (opens the source at this quote in a new tab)

“These data suggest that LAMP-2B, but not LAMP-2A or LAMP-2C, is required for autophagy in human CMs.” (opens the source at this quote in a new tab)

“Taken together, these results demonstrate that LAMP-2B is specifically responsible for metabolic defects in Danon hiPSC-CMs.” (opens the source at this quote in a new tab)

“In hiPSC-CMs, deletion of the LAMP-2B isoform decreased total LAMP-2 protein expression by more than 70%.” (opens the source at this quote in a new tab)

Expression cassette and promoter

“To investigate the potential of gene therapy for the treatment of DD, we created an AAV9 vector overexpressing human LAMP2B (AAV9.LAMP2B) in collaboration with the University of Pennsylvania viral vector core.” (opens the source at this quote in a new tab)

“Transgene expression is under the control of the constitutively active CAG promoter, consisting of a cytomegalovirus” (opens the source at this quote in a new tab)

“This constitutively active promoter was chosen to allow for LAMP2B isoform expression in multiple tissues because DD is a multiorgan disorder (22).” (opens the source at this quote in a new tab)

“(A) The pAAV-LAMP2B transfer plasmid (pAAV_CB7.Cl.LAMP- 2B.WPRE.rBG) contains this expression cassette flanked by viral ITR regions derived from AAV2.” (opens the source at this quote in a new tab)

Single administration and the durability rationale in non-dividing cardiomyocytes

“Non-dividing, terminally differentiated cardiomyocytes are transduced” (opens the source at this quote in a new tab)

“RP-A501 encodes full-length, wild-type LAMP2B; cardiomyocytes are non-dividing cells” (opens the source at this quote in a new tab)

“The cardiomyocyte is a long-lived, postmitotic cell that contracts continuously and cannot dilute damaged components through cell division.” (opens the source at this quote in a new tab)

“RP-A501 represents a single dose treatment and is administered as an intravenous infusion.” (opens the source at this quote in a new tab)

“Single-dose infusion: Treatment is given only once, as a single intravenous (IV) infusion.” (opens the source at this quote in a new tab)

Absence of an opportunity to re-dose

“Finally, the inability to re-dose due to neutralizing antibody formation remains a major limitation of current AAV platforms, emphasizing the importance of first-dose optimization and long-term durability assessment.” (opens the source at this quote in a new tab)

“Indeed, sustained high-titer antibody levels following systemic AAV-mediated gene therapy may prevent the possibility of re-administration of cross-reacting AAV therapies in humans.” (opens the source at this quote in a new tab)