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A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept Studies

2: Bicistronic AAV Gene Therapy for Tay-Sachs and Sandhoff Diseases in the Sheep Model of Tay-Sachs

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Gene Therapy in Large Animal Models
Location: Room 204
Start Time: 5/16/2022 10:30
End Time: 5/16/2022 10:45

Tay-Sachs and Sandhoff diseases (TSD, SD) are fatal neurodegenerative disorders, caused by mutations in alpha or beta subunit respectively, of the enzyme Hexosaminidase A (HexA). Hex A deficiency results in GM2 ganglioside storage and subsequent neuronal death. Here we report on the preclinical therapeutic efficacy of a bicistronic AAV9 vector in TSD sheep after intravenous (IV, n=5) or cerebrospinal fluid injection by combined bilateral ventricular injection, cisternal magna and lumbar intrathecal injection (CSF, 1E14 vg n=5 long term; n= 4 short term end point at 5 months). Sheep treated IV survived to 18±5 months and CSF treated sheep are ongoing with the oldest now more than 4 years old (untreated TSD sheep survive ~ 9±0.5 months). Both IV and CSF treated TSD sheep exhibited marked attenuation of neurologic disease as well as normal cognition as measured by maze testing. GM2 ganglioside and HexA levels in CSF normalized by 1 month after CSF administration and remained at normal range. CSF GM2 in the IV cohort were intermediate of TSD and normal sheep. No increase in Hex A levels in serum was noted in either the IV or CSF cohorts. Magnetic resonance spectroscopy (MRS) showed normalization of markers of neuronal health, myelination, and metabolism in the CSF treated cohort and partial improvement in the IV cohort. Diffusion tensor imaging (DTI) demonstrated the decrease in microstructural integrity and increase in water diffusion through white matter of TSD thalamus. In line with MRS findings, CSF and IV treatment normalized the abnormalities of white matter structure. The CSF treated cohort had serum anti AAV9 neutralizing antibodies (Nab) > 1:10 and 1:20 at the time of treatment that increased to a maximum of 1:160. CSF treatment resulted in at or above normal Hex A levels (3X-20X) throughout the brain and spinal cord. IV treatment resulted in Hex A activity in spinal cord at ~ 70% and 100% of normal level in cervical and lumbar sections, ~ 20% in cerebellum and brainstem and low levels in other brain regions (up to 10%). CSF treatment normalized GM2 levels in brain and spinal cord, with the exception of the thalamus and temporal cortex where GM2 levels decreased by 50%. IV treatment lowered GM2 levels to ~30% of TSD in cervical and lumbar spinal cord, while GM2 levels in brain remained at untreated TSD levels. Vector biodistribution in CNS is in line with Hex A expression. Partial normalization in peripheral nerve was noted in both the IV and CSF cohorts. QPCR detected up to 10X higher copy number for IV cohort in autonomic nerves (vagus, sympathetic chain and vago-sympathetic trunk), but was not reflected by Hex A levels. CSF treatment, increased Hex A levels to 10% normal in muscle and ~7% normal in liver. IV treatment normalized Hex A levels in muscle and resulted in 10% normal Hex A activity in heart and spleen and ~4% normal in liver. The increase in Hex A was sufficient to decrease GM2 levels to below 50% TSD level in heart, muscle, and liver in both cohorts. Change in Hex A levels for both cohorts were not sufficient to decrease GM2 levels in spleen, lung and kidney as compared to TSD. These data show promise for a minimally invasive treatment for TSD and SD using this bicistronic vector construct, which provided the basis for submission of a pre-IND application.

Toloo Taghian1, William C. Baker1, Stephanie Bertrand2, Abigail W. McElory1, Hector R. Benatti1, Jillian Gallagher1, Erin Hall1, Deborah Fernau1, Kalajan L. Mercado3, Lauren Ellis3, Elise Diffie4, Amanda Gross3, Anne S. Maguire3, Monique Otero1, Rachel Prestigiacomo2, Rachael Gately2, Hannah Lahey1, Ana Rita Batista1, Amanda Taylor3, Jey Koehler3, Douglas R. Martin3, Miguel Sena-Esteves1, Heather L. Gray-Edwards1

1UMass Chan Medical School, Worcester, MA,2Tufts Cummings School of Veterinary Medicine, Grafton, MA,3Auburn University, Auburn, AL,4Auburn Univeristy, Auburn, AL
 T. Taghian: None.

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