It appears that the pre-clinical results are very very good for the Bicistronic AAV gene therapy for Tay-Sachs and Sandhoff diseases in a sheep model especially when injected via cerebrospinal fluid (CSF)
"...CSF treated sheep are ongoing with the oldest now more than 3 years old. Untreated TSD sheep reach humane endpoint at ~9 months...."
"...GM2 levels in CSF of sheep treated by CSF administration were normalized starting at 1 month after treatment and remained in normal range up to 2 years...."
"...CSF treatment resulted in HexA activity at above normal levels in central nervous system (CNS)...."
"...Magnetic resonance spectroscopy of treated sheep thalamus showed normalization of neuronal health markers, myelination and metabolism in CSF cohort...."
"...Both cohorts exhibited marked attenuation of neurologic disease and normal cognition in neurological examination...."
Bicistronic AAV gene therapy for Tay-Sachs and Sandhoff diseases in a sheep model
T Taghian D Fernau K Mercado L Ellis E Diffie A Gross A Maguire A Batista S Bertrand M Otero R Prestigiacomo R Gately J Gallagher H Lahey A Taylor J Koehler D Martin M Sena-Esteves1 H Gray-Edwards
1: University of Massachusetts Medical School 2: Auburn University 3: Tufts Cummings School of Veterinary Medicine
Tay-Sachs and Sandhoff diseases (TSD, SD) are fatal neurodegenerative disorders, caused by mutations in alpha or beta subunit of enzyme Hexosaminidase (Hex), respectively, and result in GM2 ganglioside storage and neuronal death. Here we describe therapeutic efficacy of a bicistronic AAV9 vector construct in naturally occurring sheep model of TSD. TSD sheep were injected with 1E14 vg total intravenously (IV, n=5) or via cerebrospinal fluid (CSF, n=9). Sheep treated IV survived to 18?±?5 months and CSF treated sheep are ongoing with the oldest now more than 3 years old. Untreated TSD sheep reach humane endpoint at ~9 months. GM2 levels in CSF of sheep treated by CSF administration were normalized starting at 1 month after treatment and remained in normal range up to 2 years, however, GM2 levels in IV cohort remained above normal. CSF treatment resulted in HexA activity at above normal levels in central nervous system (CNS), however, for IV cohort only lumbar spinal cord reached normal level. HexA expression in peripheral nervous system (PNS) was similar for both cohorts. GM2 levels in CNS and PNS were in line with HexA levels. Vector genome content in CNS was consistent with HexA levels, however, IV treatment except for optic nerve resulted in higher number of virus particles in PNS. Magnetic resonance spectroscopy of treated sheep thalamus showed normalization of neuronal health markers, myelination and metabolism in CSF cohort and slight improvements in IV cohort. Both cohorts exhibited marked attenuation of neurologic disease and normal cognition in neurological examination.
Good luck and GOD bless,
