A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice

• Published in: Molecular therapy. Methods & clinical development Vol. 32; no. 2; p. 101269
• Main Authors: Sangster, Madison L., Bishop, Martha M., Yao, Yizheng, Feitor, Jessica F., Shahriar, Sanjid, Miller, Maxwell E., Chekuri, Anil K., Budnik, Bogdan, Bei, Fengfeng, Grishchuk, Yulia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-06-2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; adeno-associated vector; gene transfer; lysosomal disorder; mouse model; Original; pediatric neurological disease; TRPML1; TRPML1; gene transfer; mouse model; AAV; pediatric neurological disease; lysosomal disorder; adeno-associated vector
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2024.101269

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1−/− mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.
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MLIV is a rare neurological disease of childhood with extremely high unmet need. Here, Grishchuk and colleagues show that AAV-CPP16-mediated gene transfer of the MLIV causative MCOLN1 gene to symptomatic MLIV mice restores neurofunction, delays paralysis, and alleviates brain pathology, indicating a promising therapeutic approach for clinical development.