Development Of An In Vitro Potency Assay For An AAV Gene Therapy Delivering A Functional Version Of SHANK3

Patients with SHANK3 haploinsufficiency suffer from debilitating neurodevelopmental disorders, including Phelan-McDermid syndrome (PMS). This condition is characterized by severe intellectual disabilities, impaired or absent speech and language, deficits in motor skills, behavioral challenges, and features of autism. SHANK3 is primarily found in glutamatergic synapses, where it plays a crucial role in regulating postsynaptic signaling by acting as a molecular scaffold through interactions with other proteins in the postsynaptic density.

To address SHANK3 haploinsufficiency caused by loss-of-function mutations, JAG201 is an AAV9-based gene therapy designed to deliver a functional version of the SHANK3 protein. To support product development, an in vitro assay was established to characterize the potency of JAG201. This assay is grounded in the mechanism of action (MOA) of SHANK3, where the protein acts as a scaffold within the postsynaptic density.

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