Title : Development of NtBuHA as a small molecule therapeutic for CLN1 batten disease: An update on research efforts
Abstract:
Introduction:
Infantile Neuronal Ceroid Lipofuscinosis (INCL, also known as CLN1 Batten Disease, or CLN1) is a rare, devastating neurodegenerative disease affecting infants and children. CLN1 is caused by mutations in the CLN1 gene, which encodes the enzyme palmitoyl-protein thioesterase-1 (PPT1), an important regulator of protein palmitoylation. Based on previous work done by Dr. Anil Mukherjee at the NIH that demonstrated N-tert-butyl-hydroxylamine (NtBuHA) mimicked the activity of PPT1, Circumvent recognized the potential of NtBuHA as an effective drug for CLN1 and elected to pursue more rigorous studies to justify investing in an IND-enabling program – including proteomics analysis, toxicology, and CLN1 mouse studies.
Methods:
In collaboration with Dr. Akira Yoshii’s Lab at the University of Chicago, CLN1 PPT1 knockout mice have been treated with varying doses of NtBuHA and after sacrifice have been evaluated for reduction in markers for neuroinflammation and lysosomal inclusions. Circumvent has also run proteomics studies and Acyl-RAC based studies on palmitoylation on CLN1 patient brain tissue to identify alterations in palmitoylation of the proteome as well as protein expression that may be used as biomarkers for patient recruitment for future clinical trials. A GLP-compliant IND-enabling program is currently being conducted on a proprietary salt-form of NtBuHA with the first in-vivo pivotal study scheduled for Q1 of 2023.
Results:
Ongoing animal studies have recapitulated the efficacy of NtBuHA in reducing the prevalence of lipofuscin deposits by over 50% in vitro (P<.0001). Additionally, 2 month old mice treated with NtBuHA saw a significant reduction in multiple markers of neuroinflammation (P=.0025, .0004,<.0001). Both in vitro and in vivo toxicology experiments demonstrated no significant toxicity. No pilot toxicities (pilot rat 7-day MTD, mouse 280-day exposure at therapeutic doses, in-vitro GLP genotoxicology AMES/micronucleus) have been observed.
Conclusion:
These promising initial results provide further evidence that NtBuHA is a promising potential therapeutic for CLN1 patients and warrants continuation of ongoing investigations for thioesterase deficiencies. If successful, CIRC827 would be the only therapeutic available to treat CLN1.
Disclosure: Funding provided by NIH SBIR Phase 1 Grant (NIA 1R43AG072984-01), NIH STTR (NICHD 1R41HD105560-01), NIH SBIR Phase 2 Grant (NINDS 5R44NS120360-02)
Acknowledgements: Dr. Anna Scott at Seattle Children's Hospital, Dr. Akira Yoshii and collaborators at the University of Illinois Chicago, and Dr. Michael Forrester and collaborators at Duke University
