Researchers have developed a novel folate-modified polyamidoamine dendrimer (FP-CDE) to deliver a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) expression vector targeting the transthyretin (TTR) gene, TTR-CRISPR plasmid DNA (pDNA), to retinal tissues.

This represents a potential strategy for the treatment of ocular manifestations associated with hereditary transthyretin amyloidosis (hATTR).

“Based on the in vivo experiments showing the excellent safety of FP-CDE/TTR-CRISPR pDNA, FP-CDE is expected to be applied as the TTR-CRISPR pDNA retinal delivery carrier for treatment of [hATTR] ocular amyloidosis,” the authors said.

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The novel system was taken up by retinal pigment epithelial cells via folate receptor-α-mediated endocytosis, and it allowed for a higher suppressive effect on TTR messenger RNA production than the control CRISPR pDNA complex. The suppressive effect was maintained after cell passaging, suggesting that the FP-CDE/TTR-CRISPR pDNA complex might enable the knockout of the TTR gene. Moreover, the FP-CDE/TTR-CRISPR pDNA system showed inhibitory and breaking effects on TTR Val30Met amyloid formation in vitro.

The researchers performed a preliminary study to evaluate the potential therapeutic effect of the FP-CDE/TTR-CRISPR pDNA system in vivo. They administered the FP-CDE/pDNA solution as an eye drop to assess the gene transfer activity of FP-CDE/TTR-CRISPR pDNA in healthy mice and found that FP-CDE had an approximately 5-fold higher gene transfer effect in the whole eye than CDE.

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However, the evaluation of retinal migration of CDE and pDNA suggested that the carrier system needs further optimization to deliver pDNA to retinal pigment epithelial cells with high selectivity.

The researchers are now preparing to assess long-term genome editing effects and the safety of the FP-CDE/TTR-CRISPR pDNA system in an in vivo hATTR ocular amyloidosis model.


Inoue M, Muta K, Mohammed AFA, et al. Feasibility study of dendrimer-based TTR-CRISPR pDNA polyplex for ocular amyloidosis in vitro. Biol Pharm Bull. 2022;45(11):1660-1668. doi:10.1248/bpb.b22-00452