期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 20, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI163107
关键词
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资金
- National Institute of Neurological Disorders and Stroke (NINDS) , NIH [R43 NS107079, R43NS107079-01S1, 3R43NS107079-01S2]
- NINDS, NIH [R56 NS117635, R01 NS124655, R01 NS100779]
- Haley's Heroes project grant
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J004316/1, BB/P013732/1]
- RS Macdonald Charitable Trust
- Department of Pediatrics, Washington University in St. Louis, School of Medicine
- McDonnell International Scholars Academy award
CLN1 disease, a fatal neurodegenerative lysosomal storage disorder, has proven challenging to treat. This study tested the efficacy of enzyme replacement therapy (ERT) and found that intracerebrovascular administration of recombinant PPT1 showed therapeutic benefits in mouse and sheep models. The findings highlight the feasibility and therapeutic efficacy of ERT and emphasize the importance of cross-species research in developing successful treatment strategies.
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.
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