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A - Viral Vector Development -> AAV Vectors – Clinical/Non-Human Primate Studies

1099: coAAV Vectors from the AAV-Ligand Conjugate (ALIGATER™) Platform Outperform AAV9 to Address Neurological Disorders via CSF Delivery

Type: Poster Session

Poster Board Number: 1099
Presentation Details
Session Title: Thursday Poster Session
Start Time: 5/18/2023 12:00
End Time: 5/18/2023 14:00

Adeno-associated virus (AAV) is the vector of choice for in vivo gene therapy. One of its most exciting advantages lies in its versatility in terms of applications and routes of administration (RoA). Consequently, the AAV platform has evolved quickly over the past decade, moving from the historical natural capsids to hundreds of new synthetic variants, all with their own set of transduction properties. The technology however still faces many challenges and improving features such as vector spreading from the delivery site, AAV transduction and transgene expression, or the immune profiles of AAVs still concentrates a lot of efforts worldwide. Many are focused on modifying the capsid at a genomic level to meddle with epitopes involved in cell tropism. Such genetic mutations, however, can destabilize AAV formation, negatively affecting downstream processes and production titers. And in any case, such genetic variants warrant the development of a dedicated CMC process, which can considerably slow the translation of a therapeutic vector to the clinic. The AAV-Ligand Conjugate (ALIGATER™) platform is a robust alternative to capsid genetic engineering, which relies on the chemical conjugation of small, functionalizing ligands at the surface of the AAV capsid. As it requires no prior genetic intervention and is performed on AAV post production, this platform can be applied easily to virtually any natural or engineered AAV serotype. Here, we demonstrate that ALIGATER™ is particularly exciting for applications in the central nervous system (CNS). Building on our initial results with conjugated AAV (coAAV) vectors, showing improved brain distribution and transduction following intra parenchymal delivery in both rodents and non-human primates (NHP), we investigated the performance of coAAVs in the brain when administered directly into the cerebrospinal fluid (CSF) - a safer delivery procedure than the one tested before. To this end, we built a library of coAAVs and performed a parallel evaluation of these vectors with AAV9 in the NHP brain following intra-cisterna magna (ICM) delivery. Whereas AAV9 is considered as one of the best-in-class serotypes to effectively transduce the brain via this RoA, some serious adverse events have been reported following its use in both primate studies and clinical trials. Safety concerns were largely linked to dorsal root ganglion (DRG) and liver toxicities, resulting from elevated transduction and transgene expression levels in organs. In this study, we showed that at equivalent doses, several coAAVs presented biodistribution and transduction profiles comparable to AAV9 in the brain, while displaying low levels of transduction and transgene expression in the DRGs and most peripheral tissues. These results thus demonstrate that ALIGATER™ is a safe and efficient platform for neurological applications. It can be used to generate strong and robust proof of concept studies in small animals with good translatability to larger animals, accelerating the development of safe therapeutic vectors for neurological disorders.

Alexianne Gougerot1, Adrien Savy1, Nitza Thomasson2, Kamelia Kara-Ali1, Lavaniya Kunalingam1, Ludmila Juricek1, Patrice Vidal1, Gaelle M. Lefevre1

1COAVE THERAPEUTICS, Paris, France,2NTZ Consulting, Paris, France
  G.M. Lefevre: 1; Commercial Interest i.e. Company X; COAVE THERAPEUTICS. 1; What was received? i.e. Honorarium; Salary. 1; For what role? i.e. Speaker; Employment.

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