June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
CTx001, a gene therapy for the treatment of geographic atrophy in aged-related macular degeneration
Author Affiliations & Notes
  • Dennis Keefe
    Complement Therapeutics, London, United Kingdom
  • Mustafa Munye
    Complement Therapeutics, London, United Kingdom
  • Rafiq Hasan
    Complement Therapeutics, London, United Kingdom
  • Sonika Rathi
    Department for Ophthalmology, University Eye Clinic, Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • Paul Bishop
    Division of Evolution, Infection and Genomics, The University of Manchester Faculty of Biology Medicine and Health, Manchester, United Kingdom
  • Simon Clark
    Department for Ophthalmology, University Eye Clinic, Eberhard Karls Universitat Tubingen, Tubingen, Baden-Württemberg, Germany
  • Footnotes
    Commercial Relationships   Dennis Keefe Complement Therapeutics, Code E (Employment); Mustafa Munye Complement Therapeutics, Code E (Employment), Complement Therapeutics, Code P (Patent); Rafiq Hasan Complement Therapeutics, Code E (Employment), Complement Therapeutics, Code P (Patent); Sonika Rathi None; Paul Bishop Complement Therapeutics, Code C (Consultant/Contractor), Complement Therapeutics, Code O (Owner), Complement Therapeutics, Code P (Patent); Simon Clark Complement Therapeutics, Code C (Consultant/Contractor), Complement Therapeutics, Code O (Owner), Complement Therapeutics, Code P (Patent)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3852. doi:
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    • Get Citation

      Dennis Keefe, Mustafa Munye, Rafiq Hasan, Sonika Rathi, Paul Bishop, Simon Clark; CTx001, a gene therapy for the treatment of geographic atrophy in aged-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3852.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) is strongly associated with genes that regulate the alternative complement pathway. Complement Therapeutics is developing CTx001, an AAV gene therapy expressing a soluble, truncated form of complement receptor 1 (mini-CR1) for the treatment of geographic atrophy (GA).

Methods : In vitro assays were performed using recombinant mini-CR1 produced in HEK cells. Binding assays were performed using surface plasmon resonance, C3b cleavage was quantified by SDS-PAGE, and assembly of the membrane attack complex (MAC) was assessed in zymosan activated human serum (Weisslab assay). The diffusion properties of mini-CR1 were characterized ex vivo in Ussing chambers containing Bruch’s membrane enriched from human donor eyes. Transduction of human RPE cells with AAV2 expressing mini-CR1 (CTx001) was assessed by qRT-PCR and Western blot. In vivo pharmacology of CTx001 following subretinal injection was assessed in the murine laser induced model of choroidal neovascularization (CNV).

Results : Mini-CR1 bound C3b (KD = 20nM) and its cofactor driven proteolysis of C3b by factor I resulted in >90% degradation within one hour. Mini-CR1 and native CR1 showed similar cofactor activity. Mini-CR1 cofactor activity drove proteolysis of C3b to the terminal C3dg fragment, and prevented MAC formation in human serum (IC50 = 125nM). Prevention of MAC formation by mini-CR1 was not attenuated in the presence of supraphysiological levels of all five Factor H related (FHR) proteins, which are elevated in some GA patients and are known antagonists of C3b cleavage. Mini-CR1 successfully crossed enriched Bruch’s membrane derived from human donor eyes ex vivo and maintained cofactor activity. Mini-CR1 expression following CTx001 transduction of RPE cells was dose proportionate, and secretion was verified by Western blot. Mini-CR1 expression in murine eyes following subretinal injection of CTx001 was dose proportionate, and MAC formation following laser induced CNV was reduced by 65% and 69% relative to null vector at 5x108 and 5x109 vector genome copies, respectively. No adverse findings were reported following subretinal CTx001 delivery.

Conclusions : CTx001 is a potent negative regulator of the alternative complement pathway and in vivo findings suggest it is safe, well tolerated and pharmacologically active. Continued development of CTx001 for the treatment of GA is therefore warranted.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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