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
View: Text | PDF
Research Article Development

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

×

Figure 3

HexA activity and GM2 ganglioside levels in CNS after bicistronic AAV administration.

Options: View larger image (or click on image) Download as PowerPoint
HexA activity and GM2 ganglioside levels in CNS after bicistronic AAV ad...
(A) Dorsoventral view of the sheep brain, with white lines showing corresponding brain sections. (B) Analyzed regions include frontal cortex (FC), parietal cortex (PC), thalamus (Th), temporal cortex (TC), occipital cortex (OC), cerebellum (CB), brainstem (BS), cervical intumescence (CI), and lumbar intumescence (LI). (C) HexA activity. Short-term TSD+AAV_CSF_ICV-CM-LIT cohort (pink hexagon) had HexA levels similar to or higher than WT (gray circles) levels in all analyzed CNS regions and were not significantly different from WT at 5 months. The TSD+AAV_IV cohort had significantly less HexA levels in all analyzed region as compared with WT except for Thal, CI, and LI. (D) GM2 ganglioside. Short-term TSD+AAV_CSF_ICV-CM-LIT cohort (pink hexagon) had HexA levels similar in same range as WT (gray circles) levels in all analyzed CNS regions and were not significantly different from WT at 5 months except for striatum. TSD+AAV_IV cohort had significantly higher GM2 levels as compared with WT (not significantly different from TSD) in all analyzed regions except for CI and LI, where no statistical difference was obtained as compared with WT (note: this might be due to variability in data). Brown-Forsythe and Welch’s ANOVA tests followed by Dunnett’s T3 test were performed for statistical analysis in C and D. Assays were repeated at least 3 times.