A blood-brain-barrier penetrant AAV gene therapy rescues neurological deficits in mucolipidosis IV mice

• DOI: 10.1101/2023.11.03.565568
• Publication Date: 2023-11-05T23:35:11Z
• Authors: Madison Sangster; Martha Bishop; Yizheng Yao; Jessica Feitor; Sanjid Shahriar; Maxwell Miller; Anil K. Chekuri; Bogdan Budnik; Fengfeng Bei; Yulia Grishchuk
• Keywords: Lysosomal storage disease

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