Preclinical pharmacology and safety of GT005, an investigational gene therapy targeting the complement pathway for the treatment of Geographic Atrophy

Abstract

Purpose : Report preclinical pharmacology and safety data of GT005, an investigational AAV2 expressing recombinant human Complement Factor I (hCFI), after subretinal delivery in non-human primates (NHP).

Methods : GT005 was assessed in a 6-month NHP GLP toxicology study after subretinal injection at low dose (LD) 7x10¹⁰ and high dose (HD) 3.5x10¹¹ vg/eye (3 animals/sex/dose). Optical coherence tomography, intraocular pressure, electroretinography, vector shedding, ELISPOT, antibodies to capsid and hCFI, and hCFI levels in vitreous humor (VH) were measured throughout the study. Histopathology, vector biodistribution and hCFI expression in tissue were evaluated at termination.

Results : There were no systemic effects of GT005 and no treatment-related findings outside the eye. There were histopathology findings in the injection area for both doses, with variable severity. Mononuclear cell infiltrates were found in ocular tissues, optic nerve, optic disk, VH and iris/ciliary body. Loss of RPE and photoreceptors was detected from week (wk) 13. These changes correlated with a significant anti-hCFI antibody response in serum and VH of most treated NHPs at wk 13 and 26 (P<0.01). Serum levels of antibodies to AAV2 at wk 4 were weaker and remained constant at wk 13 and 26. No T cell responses to hCFI or AAV2 were found in NHPs, except for one animal in the HD group which developed a significant response against AAV2. Vector biodistribution was similar for both doses with levels highest at the dose site in ocular tissues and falling to below the limit of detection in most organs. Vector shedding was confined to tear samples up to wk 4. hCFI mRNA and protein expression was observed in the outer retina and hCFI protein was detected in VH from 2 wks up to 26 wks. Maximal levels of hCFI were found in the VH at wk 4 in the HD (1437±551 ng/mL) and at wk 13 in the LD (805±249 ng/mL). Reduced hCFI levels at later timepoints correlated with antibody titres to hCFI (R=0.83; P<0.001).

Conclusions : GT005 was well tolerated with no safety findings outside the eye. GT005 led to local hCFI expression. Ocular dose-dependent inflammation-induced changes were observed, and correlated strongly with anti-hCFI antibody generation. These were deemed to be species-specific and therefore unlikely to translate to the clinic. These data supported the clinical development of GT005.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.