AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

Xin Chen; Thomas Dong; Yuhui Hu; Frances C. Shaffo; Nandkishore R. Belur; Joseph R. Mazzulli; Steven J. Gray

doi:10.1172/JCI146286

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dosedependent effects. A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.

Original language	English (US)
Article number	e146286
Journal	Journal of Clinical Investigation
Volume	132
Issue number	5
DOIs	https://doi.org/10.1172/JCI146286
State	Published - Mar 1 2022

Funding

This study was supported primarily by funding from Mila’s Miracle Foundation, with additional funding from the Batten Hope Foundation to SJG. We thank Jackson Laboratories for providing the initial mouse breeders and UNC and Vigene Biosciences for producing the vectors used in these studies. We thank Shari Birnbaum and her team at the UTSW Phenotypic Core Facility for performing all the behavioral tests. We acknowledge Mary Wight-Carter and her team at the UTSW Diagnostic Laboratory for their toxicity evaluation and histopathological safety report. IND application 19766 to initiate a phase I intrathecal gene transfer trial for AAV9/MFSD8 was approved by the FDA in December 2020, and the trial is currently enrolling CLN7 patients at Children’s Health in Dallas, Texas, USA, in collaboration with the UTSW Medical Center (Clinical-Trials.gov NCT04737460).

ASJC Scopus subject areas

General Medicine

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title = "AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease",

abstract = "Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dosedependent effects. A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.",

author = "Xin Chen and Thomas Dong and Yuhui Hu and Shaffo, {Frances C.} and Belur, {Nandkishore R.} and Mazzulli, {Joseph R.} and Gray, {Steven J.}",

note = "Funding Information: This study was supported primarily by funding from Mila{\textquoteright}s Miracle Foundation, with additional funding from the Batten Hope Foundation to SJG. We thank Jackson Laboratories for providing the initial mouse breeders and UNC and Vigene Biosciences for producing the vectors used in these studies. We thank Shari Birnbaum and her team at the UTSW Phenotypic Core Facility for performing all the behavioral tests. We acknowledge Mary Wight-Carter and her team at the UTSW Diagnostic Laboratory for their toxicity evaluation and histopathological safety report. IND application 19766 to initiate a phase I intrathecal gene transfer trial for AAV9/MFSD8 was approved by the FDA in December 2020, and the trial is currently enrolling CLN7 patients at Children{\textquoteright}s Health in Dallas, Texas, USA, in collaboration with the UTSW Medical Center (Clinical-Trials.gov NCT04737460). Publisher Copyright: {\textcopyright} 2022 American Society for Clinical Investigation. All rights reserved.",

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AU - Belur, Nandkishore R.

AU - Mazzulli, Joseph R.

AU - Gray, Steven J.

N1 - Funding Information: This study was supported primarily by funding from Mila’s Miracle Foundation, with additional funding from the Batten Hope Foundation to SJG. We thank Jackson Laboratories for providing the initial mouse breeders and UNC and Vigene Biosciences for producing the vectors used in these studies. We thank Shari Birnbaum and her team at the UTSW Phenotypic Core Facility for performing all the behavioral tests. We acknowledge Mary Wight-Carter and her team at the UTSW Diagnostic Laboratory for their toxicity evaluation and histopathological safety report. IND application 19766 to initiate a phase I intrathecal gene transfer trial for AAV9/MFSD8 was approved by the FDA in December 2020, and the trial is currently enrolling CLN7 patients at Children’s Health in Dallas, Texas, USA, in collaboration with the UTSW Medical Center (Clinical-Trials.gov NCT04737460). Publisher Copyright: © 2022 American Society for Clinical Investigation. All rights reserved.

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N2 - Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dosedependent effects. A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.

AB - Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8- /- mice at P7-P10 or P120 with high or low dose led to clear age- and dosedependent effects. A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.

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AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

Abstract

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ASJC Scopus subject areas

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