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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Subretinal gene therapy fails to improve vision in AMD patients

An investigator-sponsored Phase 1/2a clinical trial to assess the safety and 3-year results of subretinal gene therapy has failed to improve vision in patients with wet age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries and currently no treatment is available for late-stage AMD. Overexpression of vascular endothelial growth factor (VEGF) has been linked to the neovascular form of AMD, wet AMD (wAMD) anti-VEGF molecules such as ranibizumab has been shown to be effective for treating wAMD. More recently, downregulation of a naturally occurring VEGF inhibitor, soluble fms-like tyrosine kinase-1 (sFLT-1), was shown to be linked to wAMD and sFLT-1 alone was able to rescue neovascularization in rodent and primate models.

Given the potential of recombinant adeno-associated virus vector gene-therapy for longer-term control or reversal of pathogenic processes, researchers at Lions Eye Institute, Nedlands Australia developed a gene therapy strategy (rAAV.sFLT-1) to treat wAMD.

The Phase 1 study proved the safety of rAAV.sFLT-1 administered subretinally to 6 patients with advanced wAMD. A Phase 1/2 study was further conducted to investigate the safety and efficacy of rAAV.sFLT-1 gene therapy delivered subretinally (1X1011vg rAAV.sFLT-1) to 24 patients with active wAMD compared to 13 control patients. Results published in 2016 in EBiomedicine 12 months after the treatment showed the treatment to be safe and promising. The patients were monitored for another two years and the results were published recently in the American Journal of Ophthalmology.

During the 3 years, patients received anti-VEGF retreatment injections and at 12 months, gene therapy patients were divided into two groups: HD-1 (n=14), requiring <2 and HD-2 (n=10) requiring >2 retreatments.

Results showed that the treatment was well-tolerated by the patients. Control patients received a median of 7 retreatments, lost a median of 7.0 early treatment diabetic retinopathy study (ETDRS) letters, HD-1 patients received a median of 2.5 retreatments, lost a median of 4.0 ETDRS letters and HD-2 patients received a median of 11.0 retreatments, lost a median of 7.0 ETDRS letters over 3 years. Four HD-1 patients (34%) maintained significant visual improvement at 3 years but none of these observations were statistically significant.

The combined Phase 1/2 trial showed that the treatment was safe in the elderly. Although a positive efficacy trend was seen in the patients who received gene therapy, it was not statistically significant, implying this particular subretinal gene therapy is not a viable option for wet AMD.

Source: Three-year follow-up of Phase 1 and 2a rAAV.sFLT-1 subretinal gene therapy trials for exudative age related macular degeneration. Rakoczy EP et al., Americal Journal of Ophthalmology, March 2019. DOI

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