Treatment of GM1 gangliosidosis CNS manifestations by AAV systemic expression of lectin-enhanced enzyme

BioStrategies LC proposes to complete IND-enabling studies to advance the development of BIOS-GM1, a
novel drug therapy combining a delivery enhanced replacement enzyme with gene therapy to treat GM1
gangliosidosis. BIOS-GM1 would provide patients corrective doses of enzyme to the CNS to prevent the
debilitating symptoms of GM1 gangliosidosis including neurologic, psychomotor deficiencies, and premature
death. GM1-gangliosidosis is a neurosomatic lysosomal storage disease linked to mutations in the GLB1 gene
that encodes lysosomal acid β-galactosidase (β-Gal). The hallmark of GM1 is accumulation of the
glycosphingolipid GM1-ganglioside (GM1), particularly in neurons. No therapy has been approved for this
disease, in part because of the difficulty in transporting potential drug therapy across the blood brain barrier
(BBB) or transfecting the CNS tissue. In contrast to other gene therapies in development for GM1 gangliosidosis,
BioStrategies’ approach is designed to achieve a systemic therapeutic effect, including delivery of a functional
replacement enzyme across the blood brain barrier (BBB) without intrathecal or intraventricular administration.
This could be the first effective treatment for GM1 gangliosidosis, potentially stopping its devastating effects and
early death. It might also be a breakthrough for treating other diseases needing enzymes in both the brain and
body. In preliminary studies, BioStrategies developed a novel approach that would use AAV-based gene therapy
to deliver genes to the liver or other organs outside of the CNS to produce functional acid β-galactosidase
combined with non-toxic carbohydrate-binding subunit B of ricin (RTB), a lectin that has strong affinity for a broad
array of glycoproteins and glycolipids on mammalian cell surfaces. This RTB fusion protein is designed to
infiltrate multiple tissues, including crossing the BBB to achieve therapeutic levels in the brain. In the GM1
mouse model, intravenous administration of this product demonstrated that treatment with β-Gal:RTB showed
increased enzymatic activity in brain tissues, reduction of accumulated GM1, reversal of neuroinflammation, and
decrease in apoptotic biomarkers. The team then demonstrated that AAV-based gene therapy targeting the liver
achieved continuous production of β-Gal:RTB is able to achieve comparable therapeutic response. In this Phase
II study, we will directly test a range of AAV gene therapy vectors to identify the most effective one for production
and distribution in vivo followed by robust, fully powered efficacy testing of the best performing AAV construct in
the GM1 mouse model. Successful completion of this project is expected to provide a lead candidate to support
future IND-enabling studies. These steps are essential for obtaining an IND and advancing a product to clinical
trials. Successful development and commercialization would address a critical gap in treatment options for
patients with GM1 gangliosidosis, providing the first therapy that could effectively treat the disease.

Grant Number: 1R44NS141514-01A1
NIH Institute/Center: NIH
Principal Investigator: Walter Acosta