Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep
CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 di...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-10-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI163107 |
| _version_ | 1827768295316520960 |
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| author | Hemanth R. Nelvagal Samantha L. Eaton Sophie H. Wang Elizabeth M. Eultgen Keigo Takahashi Steven Q. Le Rachel Nesbitt Joshua T. Dearborn Nicholas Siano Ana C. Puhl Patricia I. Dickson Gerard Thompson Fraser Murdoch Paul M. Brennan Mark Gray Stephen N. Greenhalgh Peter Tennant Rachael Gregson Eddie Clutton James Nixon Chris Proudfoot Stefano Guido Simon G. Lillico C. Bruce A. Whitelaw Jui-Yun Lu Sandra L. Hofmann Sean Ekins Mark S. Sands Thomas M. Wishart Jonathan D. Cooper |
| author_facet | Hemanth R. Nelvagal Samantha L. Eaton Sophie H. Wang Elizabeth M. Eultgen Keigo Takahashi Steven Q. Le Rachel Nesbitt Joshua T. Dearborn Nicholas Siano Ana C. Puhl Patricia I. Dickson Gerard Thompson Fraser Murdoch Paul M. Brennan Mark Gray Stephen N. Greenhalgh Peter Tennant Rachael Gregson Eddie Clutton James Nixon Chris Proudfoot Stefano Guido Simon G. Lillico C. Bruce A. Whitelaw Jui-Yun Lu Sandra L. Hofmann Sean Ekins Mark S. Sands Thomas M. Wishart Jonathan D. Cooper |
| author_sort | Hemanth R. Nelvagal |
| collection | DOAJ |
| description | CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy. |
| first_indexed | 2024-03-11T12:10:19Z |
| format | Article |
| id | doaj.art-fb7adb2cd6174d5a9c38555ece25def7 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:10:19Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-fb7adb2cd6174d5a9c38555ece25def72023-11-07T16:19:27ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-10-0113220Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheepHemanth R. NelvagalSamantha L. EatonSophie H. WangElizabeth M. EultgenKeigo TakahashiSteven Q. LeRachel NesbittJoshua T. DearbornNicholas SianoAna C. PuhlPatricia I. DicksonGerard ThompsonFraser MurdochPaul M. BrennanMark GrayStephen N. GreenhalghPeter TennantRachael GregsonEddie CluttonJames NixonChris ProudfootStefano GuidoSimon G. LillicoC. Bruce A. WhitelawJui-Yun LuSandra L. HofmannSean EkinsMark S. SandsThomas M. WishartJonathan D. CooperCLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.https://doi.org/10.1172/JCI163107NeuroscienceTherapeutics |
| spellingShingle | Hemanth R. Nelvagal Samantha L. Eaton Sophie H. Wang Elizabeth M. Eultgen Keigo Takahashi Steven Q. Le Rachel Nesbitt Joshua T. Dearborn Nicholas Siano Ana C. Puhl Patricia I. Dickson Gerard Thompson Fraser Murdoch Paul M. Brennan Mark Gray Stephen N. Greenhalgh Peter Tennant Rachael Gregson Eddie Clutton James Nixon Chris Proudfoot Stefano Guido Simon G. Lillico C. Bruce A. Whitelaw Jui-Yun Lu Sandra L. Hofmann Sean Ekins Mark S. Sands Thomas M. Wishart Jonathan D. Cooper Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep The Journal of Clinical Investigation Neuroscience Therapeutics |
| title | Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep |
| title_full | Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep |
| title_fullStr | Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep |
| title_full_unstemmed | Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep |
| title_short | Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep |
| title_sort | cross species efficacy of enzyme replacement therapy for cln1 disease in mice and sheep |
| topic | Neuroscience Therapeutics |
| url | https://doi.org/10.1172/JCI163107 |
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