Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep
Toloo Taghian, Jillian Gallagher, Stephanie Bertrand, William C. Baker, Kalajan Lopez Mercado, Hector R. Benatti, Erin Hall, Yvette Lopez, Abigail McElroy, John T. McCarthy, Sanjana Pulaparthi, Deborah Fernau, Samuel Mather, Sophia Esteves, Elise Diffie, Amanda Gross, Hannah G. Lahey, Xuntian Jiang, Elizabeth Parsley, Rachael Gately, Rachel Prestigiacomo, Siauna Johnson, Amanda Taylor, Lindsey Bierfeldt, Susan Tuominen, Jennifer Koehler, Guangping Gao, Jun Xie, Qin Su, Robert King, Matthew J. Gounis, Vania Anagnostakou, Ajit Puri, Ana Rita Batista, Miguel Sena-Esteves, Douglas R. Martin, Heather Gray-Edwards
Toloo Taghian, Jillian Gallagher, Stephanie Bertrand, William C. Baker, Kalajan Lopez Mercado, Hector R. Benatti, Erin Hall, Yvette Lopez, Abigail McElroy, John T. McCarthy, Sanjana Pulaparthi, Deborah Fernau, Samuel Mather, Sophia Esteves, Elise Diffie, Amanda Gross, Hannah G. Lahey, Xuntian Jiang, Elizabeth Parsley, Rachael Gately, Rachel Prestigiacomo, Siauna Johnson, Amanda Taylor, Lindsey Bierfeldt, Susan Tuominen, Jennifer Koehler, Guangping Gao, Jun Xie, Qin Su, Robert King, Matthew J. Gounis, Vania Anagnostakou, Ajit Puri, Ana Rita Batista, Miguel Sena-Esteves, Douglas R. Martin, Heather Gray-Edwards
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Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep

Abstract

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.

Authors

Toloo Taghian, Jillian Gallagher, Stephanie Bertrand, William C. Baker, Kalajan Lopez Mercado, Hector R. Benatti, Erin Hall, Yvette Lopez, Abigail McElroy, John T. McCarthy, Sanjana Pulaparthi, Deborah Fernau, Samuel Mather, Sophia Esteves, Elise Diffie, Amanda Gross, Hannah G. Lahey, Xuntian Jiang, Elizabeth Parsley, Rachael Gately, Rachel Prestigiacomo, Siauna Johnson, Amanda Taylor, Lindsey Bierfeldt, Susan Tuominen, Jennifer Koehler, Guangping Gao, Jun Xie, Qin Su, Robert King, Matthew J. Gounis, Vania Anagnostakou, Ajit Puri, Ana Rita Batista, Miguel Sena-Esteves, Douglas R. Martin, Heather Gray-Edwards

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Figure 5

HexA activity and GM2 ganglioside levels in the nerves and peripheral organs after bicistronic AAV administration.

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HexA activity and GM2 ganglioside levels in the nerves and peripheral or...
(A) HexA activity for nerves in both TSD+AAV_IV and short-term TSD+AAV_CSF_ICV-CM-LIT (pink hexagons) cohorts showed an increase from that of the TSD controls. This was most notable for the optic, sciatic, and vagosympathetic trunk nerves; however, HexA expression in all analyzed nerves was not significantly different from the TSD controls. (B) GM2 ganglioside levels in nerves remained statistically the same as in the TSD group for both TSD+AAV_IV and short-term TSD+AAV_CSF_ICV-CM-LIT cohorts (pink hexagons) except for optic nerve in the TSD+AAV_CSF_ICV-CM-LIT cohort, which was different than in the TSD cohort (*P < 0.02). (C) HexA activity in peripheral organs remained similar to that of the TSD cohort for TSD+AAV_IV and short-term TSD+AAV_CSF_ICV-CM-LIT (pink hexagons) cohorts except for muscle. HexA was not detectable in TSD muscle. HexA in skeletal isolated from the TSD+AAV_IV group was not different from WT, while in the short-term TSD+AAV_CSF_ICV-CM-LIT (pink hexagons), HexA activity was significantly higher than in WT. (D) Levels of GM2 ganglioside in peripheral organs, except for heart and liver, remained the same as in the TSD group for both the TSD+AAV_IV and short-term TSD+AAV_CSF_ICV-CM-LIT (pink hexagons) cohorts. GM2 ganglioside levels in hearts of the short-term TSD+AAV_CSF_ICV-CM-LIT sheep were significantly lower than TSD levels (*P < 0.04). Similarly, for livers in the TSD+AAV_IV cohort, GM2 levels were significantly less than in the TSD group (*P < 0.05). Brown-Forsythe and Welch’s ANOVA tests followed by Dunnett’s T3 test were performed for statistical analysis in A–D. Assays were repeated at least 3 times. Symp chain, sympathetic chain; vago symp trunk, vagosympathetic trunk.