IND-enabling studies for Aspartylglucosaminuria (AGU) to support the initiation of an AAV9/AGA gene transfer clinical trial

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A faulty AGA gene coding for the dysfunctional enzyme results in a severe and progressive genetic neurological disorder, Aspartylglucosaminuria (AGU, OMIM # 208400). The functional enzyme is required for the breakdown of glycoproteins in the cellular lysosomes. Absence of enzymatic activity results in impaired lysosomal function and accumulation of aspartylglucosamine (GlcNAc-Asn) in the lysosomes of various tissues and body fluids. The key consequence of the substrate accumulation is lysosomal hypertrophy that manifests as intellectual disability, and other associated symptoms including skeletal and joint abnormalities. Patients have slowed/regressive psychomotor development throughout childhood, deteriorating around the third decade of life to become severely impaired mentally and physically, highly dependent on supportive care thereafter. The median lifespan of AGU patients is approximately 40-50 years. Through efforts primarily funded through a parent-organized non-profit foundation, the Rare Trait Hope Fund, Dr. Gray’s lab has generated preclinical data supporting the initiation of a Phase I/II gene therapy trial to treat AGU. A Type B preIND meeting was held with the FDA regarding this in January 2018, which has charted a clear path forward for human translation. This approach would use an AAV9/AGA vector injected intrathecally, following a precedent set by Dr. Gray’s previous efforts to initiate similar Phase I trials for Giant Axonal Neuropathy at the NIH Clinical Center in 2015 and for CLN7 Batten disease at Children’s Medical Center Dallas in 2021. The wealth of available disease-specific biomarkers for AGU (including localized imaging of the AGA enzyme substrate in discrete brain regions) along with a potentially large treatment window, make AGU an ideal disease to rapidly and fully assess the complete efficacy and/or shortcomings of intrathecal AAV9 as a “platform” approach to treat many other neurological diseases. We propose to conduct the necessary IND-enabling studies to initiate a Phase I/II clinical trial for AGU.