ABCA4-related retinopathies, including Stargardt disease, cone-rod dystrophy, and retinitis pigmentosa, lead to degeneration of rods and cones and cause vision loss that often starts in childhood or adolescence, leading to blindness.
The data demonstrate for the first time ever that a single subretinal administration of a DNA payload encoding the human ABCA4 gene resulted in durable - 12-month - expression of human ABCA4 protein in adult pig retinas, said the US biotech.
“We are highly encouraged by the promising and unprecedented findings from these preclinical studies,” said José Lora, chief scientific officer at Intergalactic.
“With these data, we have clearly demonstrated the feasibility of electro-transfer delivery of non-viral C3DNA expressing the full-length human ABCA4 gene to relevant cell types in the retina. We have also confirmed persistence of ABCA4 expression for at least 12 months in vivo in photoreceptors – the longest time point evaluated to date,” he added.
Based on the data, Intergalactic is now planning to advance its IND-enabling studies and future clinical development.
ABCA4-related retinopathies are associated with mutations in the ABCA4 gene, more than 900 of which have been described, said the developer.
“There are currently no approved treatments for ABCA4-related retinopathies and, while replacement with wild-type ABCA4 protein has the potential to slow or stop disease progression, standard AAV gene therapy platforms are not appropriate for addressing these diseases due to the large size of the gene and the growing safety concerns associated with viral vectors.
“Intergalactic’s novel platform bypasses these drawbacks and enables local delivery of non-viral gene therapy, representing a potentially transformative approach for addressing these blinding diseases,” said the Cambridge, Massachusetts based firm.
The technology
C3DNA allows for design and delivery of DNA vectors beyond the size limits of viral delivery systems.
Intergalactic said it precisely engineers C3DNA, using synthetic biology tools to assemble modular elements into a closed loop. “This covalently closed, circular (C3) construction allows C3DNA to be taken up by cells and expressed, without insertion into the host genome.”
Moreover, it says C3DNA avoids triggering an immune response, because it does not contain unintended viral or bacterial sequences. Therefore, the immune system does not ‘see’ it, enabling C3DNA to act like an endogenous gene in the nucleus, with enhanced persistence of expression, explained the biotech.
The startup also has pipeline programs targeting other ophthalmology indications and outlined how it is evaluating the broader applicability of the platform to other tissue types.
