Product information and disease description Product description Product information Pharmacology

Mechanism of action

6 evidence topics · 3 sources

Dual-transgene payload delivered by an evolved AAV capsid

“We then engineered 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA sequence that inhibits expression of VEGF-C.” (opens the source at this quote in a new tab)

Inhibition of four members of the VEGF family

“In addition, to our knowledge, 4D-150 is the first genetic medicine product candidate for the eye designed to directly inhibit four different angiogenic growth factor targets, VEGF A, B, and C plus PlGF.” (opens the source at this quote in a new tab)

Directed evolution of the R100 capsid in nonhuman primates

“We implemented a directed evolution strategy that used genetic diversification and selection processes to invent a novel AAV capsid (R100) with the capacity to transduce all major cell types across all regions of the primate retina, including the macula, following IVT administration at relatively low doses.” (opens the source at this quote in a new tab)
“After round 6, the R100 peptide insertion sequence motif represented approximately 70% of all remaining capsid sequences” (opens the source at this quote in a new tab)

Capsid structure and mechanism of inner limiting membrane penetration

“Structure–function analyses demonstrated that the 10-amino-acid peptide insertion at position R588 in the R100 capsid reduces heparin binding affinity and facilitates transit through the heparan sulfate-rich ILM, suggesting a putative mechanism for enhanced delivery to cells within the retina.” (opens the source at this quote in a new tab)

“4D-R100 was similarly engineered from an AAV2 backbone through in vivo screening in NHPs, incorporating a 10–amino acid insertion (LAISDQTKHA) at residue 588 and a VP1 point mutation at position 34 (Pro→Ala).” (opens the source at this quote in a new tab)

Rationale for targeting VEGF-C

“In addition, VEGF-C concentrations are reportedly elevated in the eye following treatment with VEGF-A inhibitors, suggesting that VEGF-A suppression induces compensatory upregulation of VEGF-C.” (opens the source at this quote in a new tab)

Promoter used in the 4D-150 transgene cassette

No evidence found.

Glycan interactions and the retinal cell types transduced by the R100 capsid

“These modifications reduce HSPG affinity and promote alternative glycan interactions (notably sialic acid), facilitating enhanced ILM penetration and efficient retinal transduction across RPE, photoreceptors, and RGCs from macula to periphery following IVT administration.” (opens the source at this quote in a new tab)