TY - JOUR
T1 - Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome
AU - Ling, Qinglan
AU - Rioux, Matthew
AU - Hu, Yuhui
AU - Lee, Min Jae
AU - Gray, Steven J.
N1 - Funding Information:
This work was supported by funding from the Cure SURF1 Foundation (now the Cure Mito Foundation) and Taysha Gene Therapies to S.J.G. We thank Dr. Massimo Zeviani and Dr. Holly Van Remmen for providing the initial SURF1 KO mice breeders, and the UNC Vector Core for producing the vectors used in these studies. We thank the UT Southwestern Metabolic Phenotyping Core for performing endurance capacity tests, measuring blood lactate, and conducting blood chemistry tests. We also thank Debby Szczepanski from the UTSW Animal Resource Center for performing intravenous injections for us. We acknowledge Dr. Mary Wright-Carter and her team at the UTSW Diagnostic Laboratory for conducting the toxicology evaluation on tissues from the safety study and providing the histopathological safety report. Q.L. and S.J.G. contributed to the study concept and design. Q.L. M.R. and Y.H. contributed to data acquisition. Q.L. and M.L. contributed to data analysis. Q.L. M.L. and S.J.G. contributed to drafting the text and figures. Q.L. and S.J.G. are inventors of the vectors used in this study, and the vectors are licensed to Taysha Gene Therapies. Q.L. and S.J.G. may receive inventor income from Taysha Gene Therapies. S.J.G. has received inventor income from Asklepios Biopharma, but that intellectual property was not used in this study. The remaining authors declare no competing interests.
Funding Information:
This work was supported by funding from the Cure SURF1 Foundation (now the Cure Mito Foundation) and Taysha Gene Therapies to S.J.G. We thank Dr. Massimo Zeviani and Dr. Holly Van Remmen for providing the initial SURF1 KO mice breeders, and the UNC Vector Core for producing the vectors used in these studies. We thank the UT Southwestern Metabolic Phenotyping Core for performing endurance capacity tests, measuring blood lactate, and conducting blood chemistry tests. We also thank Debby Szczepanski from the UTSW Animal Resource Center for performing intravenous injections for us. We acknowledge Dr. Mary Wright-Carter and her team at the UTSW Diagnostic Laboratory for conducting the toxicology evaluation on tissues from the safety study and providing the histopathological safety report.
Publisher Copyright:
© 2021 The Authors
PY - 2021/12/10
Y1 - 2021/12/10
N2 - SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.
AB - SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.
KW - AAV
KW - Leigh syndrome
KW - SURF1
KW - adeno-associated virus
KW - gene therapy
UR - http://www.scopus.com/inward/record.url?scp=85120616876&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120616876&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2021.09.001
DO - 10.1016/j.omtm.2021.09.001
M3 - Article
C2 - 34703839
AN - SCOPUS:85120616876
SN - 2329-0501
VL - 23
SP - 158
EP - 168
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -