GT005 gene therapy shows ability to modulate complement pathway in GA
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In a first-in-human phase 1/2 study, GT005, an AAV2-based one-time investigational gene therapy, showed potential to regulate the complement pathway involved in the pathogenesis of geographic atrophy.
The complement system has a key role in the pathogenesis of age-related macular degeneration, Robert MacLaren, MD, said at the virtual Euretina congress. Central to this is C3b, with an amplification cycle that leads to formation via C5 convertase of the membrane attack complex, leading to secondary damage and disruption of the retinal pigment epithelium. GT005 (Gyroscope Therapeutics) is designed to rebalance the complement system by overexpressing the complement factor I (CFI) gene, able to downregulate C3b.
In the FOCUS clinical trial, GT005 is given as a single subretinal injection to patients with geographic atrophy and is expected to maintain a long-lasting level of CFI protein in the vitreous.
“An elevation and a sustained level of CFI expression was seen in the vitreous in nine out of 10 patients so far treated. The average increase was 146% from baseline. The first patient treated continues to have sustained CFI increase at 84 weeks,” MacLaren said.
Evidence of the downregulating effects of CFI overexpression was also provided by measuring the vitreous levels of Ba and C3 breakdown products.
“Not only can we see elevated level of CFI in the vitreous, but we also can see that GT005 is functional in terms of modulating the complement pathway in the eye. A 41% reduction in Ba protein level and 42% reduction in C3 breakdown protein level in the vitreous humor as compared to baseline was observed at week 24 and 56,” MacLaren said.
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MacLaren R. Preliminary results from a first-in-human phase I/II gene therapy study (FOCUS) of GT005, an investigational AAV2 vector encoding complement factor I, in patients with geographic atrophy. Presented at: Euretina congress; Sept. 9-12, 2021 (virtual meeting).
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