June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
GT005, a gene therapy for the treatment of dry age-related macular degeneration (AMD)
Author Affiliations & Notes
  • Scott Ellis
    Gyroscope Therapeutics Ltd, Stevenage, ENGLAND, United Kingdom
  • Anna Buchberger
    Gyroscope Therapeutics Ltd, Stevenage, ENGLAND, United Kingdom
  • Julie Holder
    Gyroscope Therapeutics Ltd, Stevenage, ENGLAND, United Kingdom
  • elise Orhan
    Gyroscope Therapeutics Ltd, Stevenage, ENGLAND, United Kingdom
  • Jane Hughes
    Gyroscope Therapeutics Ltd, Stevenage, ENGLAND, United Kingdom
  • Footnotes
    Commercial Relationships   Scott Ellis, Gyroscope Therapeutics Ltd (E); Anna Buchberger, Gyroscope Therapeutics Ltd (E); Julie Holder, Gyroscope Therapeutics Ltd (E); elise Orhan, Gyroscope Therapeutics Ltd (E); Jane Hughes, Gyroscope Therapeutics Ltd (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2295. doi:
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    • Get Citation

      Scott Ellis, Anna Buchberger, Julie Holder, elise Orhan, Jane Hughes; GT005, a gene therapy for the treatment of dry age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2020;61(7):2295.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : AMD is the most common cause of blindness among the elderly in the industrialised world and accounts for 8.7% of all cases of blindness worldwide, particularly in people older than 60 years. Complement dysregulation is emerging as a key driver of AMD pathology, with genes of the alternative pathway associated with the risk of developing the disease. Gyroscope Therapeutics is developing GT005, a novel therapy that leads to the expression of human complement factor I (CFI), a negative regulator of the alternative pathway.

Methods : GT005 has been tested in several animal models to determine the pharmacodynamic, pharmacokinetic and toxicology profiles:
- human CFI expression, protein secretion, localisation and biological activity was demonstrated following subretinal injection in the mouse;
- The impact of this expression on complement activation was confirmed in the mouse laser-induced CNV model;
- GT005 toxicity, biodistribution, shedding and immunogenicity was assessed following administration of 2 doses of GT005 in GLP studies: a mouse study with a readout at 4 and 26 weeks, and a 26 week NHP study.

Results : Subretinal administration of GT005 led to a robust and dose-dependent CFI expression in the mouse eye, secretion of human CFI protein that localised to the RPE layer and was functionally active. In the mouse laser-induced CNV model, reducing complement activation by the expression of CFI led to a significant and dose-dependent reduction in choroidal neovasularisation (CNV). Subretinal administration of GT005 in both the mouse and NHP led to no adverse systemic effects and no treatment-related findings outside the retina. Inflammation-associated changes were observed in the eye that were strongly associated with the generation of anti-transgene antibodies (ATAs) to human CFI protein, and therefore were species-specific.
This data was used to support a clinical trial application; the GT005 Phase I/II clinical trial initiated in 2019 is currently ongoing, with no safety concerns to date.

Conclusions : Subretinal administration of GT005 leads to the long-term secretion of human CFI in the ocular compartment of the mouse and primate that is safe and well-tolerated. This protein is able to significantly impact complement-driven CNV in the mouse laser-induced CNV model. This data supported the initiation of the GT005 Phase I/II (FOCUS) clinical trial in patients with advanced dry AMD, currently ongoing in the UK.

This is a 2020 ARVO Annual Meeting abstract.

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