TY - JOUR
T1 - Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep
AU - Taghian, Toloo
AU - Gallagher, Jillian
AU - Bertrand, Stephanie
AU - Baker, William C.
AU - Mercado, Kalajan Lopez
AU - Benatti, Hector R.
AU - Hall, Erin
AU - Lopez, Yvette
AU - McElroy, Abigail
AU - McCarthy, John T.
AU - Pulaparthi, Sanjana
AU - Fernau, Deborah
AU - Mather, Samuel
AU - Esteves, Sophia
AU - Diffie, Elise
AU - Gross, Amanda
AU - Lahey, Hannah G.
AU - Jiang, Xuntian
AU - Parsley, Elizabeth
AU - Gately, Rachael
AU - Prestigiacomo, Rachel
AU - Johnson, Siauna
AU - Taylor, Amanda
AU - Bierfeldt, Lindsey
AU - Tuominen, Susan
AU - Koehler, Jennifer
AU - Gao, Guangping
AU - Xie, Jun
AU - Qin, Su
AU - King, Robert
AU - Gounis, Matthew J.
AU - Anagnostakou, Vania
AU - Puri, Ajit
AU - Batista, Ana Rita
AU - Sena-Esteves, Miguel
AU - Martin, Douglas R.
AU - Gray-Edwards, Heather
N1 - Publisher Copyright:
© 2025, Taghian et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2025/12
Y1 - 2025/12
N2 - Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.
AB - Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.
UR - https://www.scopus.com/pages/publications/105023550041
U2 - 10.1172/JCI182942
DO - 10.1172/JCI182942
M3 - Article
C2 - 41026525
AN - SCOPUS:105023550041
SN - 0021-9738
VL - 135
SP - 1
EP - 17
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 23
M1 - e182942
ER -