Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep
Hemanth R. Nelvagal, … , Thomas M. Wishart, Jonathan D. Cooper
Hemanth R. Nelvagal, … , Thomas M. Wishart, Jonathan D. Cooper
Published August 30, 2022
Citation Information: J Clin Invest. 2022;132(20):e163107. https://doi.org/10.1172/JCI163107.
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Research Article Neuroscience

Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep

Abstract

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.

Authors

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

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Figure 2

Improved motor performance in i.c.v. treated Cln1–/– mice.

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Improved motor performance in i.c.v. treated Cln1–/– mice. (A) Semiautom...
(A) Semiautomated gait analysis measures of average speed (cm/s), cadence (steps/second), maximum variation of speed (percentage), stride length (cm), standing time (s), swing time (s), swing speed (cm/s), and step cycle (s) from 1–6 months, showing an overall improved performance of mice treated i.c.v. with PPT1 (PPT1 i.c.v.) compared with mice treated i.c.v. with vehicle (Veh i.c.v.), and similar to WT values. (B) Stationary and constant speed rotarod tests in 5- and 6-month-old mice. The mice treated i.c.v. with PPT1 performed similarly to WT mice, whereas mice treated i.c.v. with vehicle had a statistically significant reduction in latency to fall (s) in the stationary rotarod test at 6 months. Both PPT1- and vehicle-treated mice showed a reduced latency to fall at 6 months in the constant speed rotarod test, but this did not reach statistical significance. Data represent the mean ± SEM; n = 10. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; ##P < 0.01 (WT vs. i.c.v vehicle-treated mice), by 2-way, mixed-effects ANOVA with post hoc Bonferroni’s correction (see Supplemental Data File 2 for full P values).