Measuring neurotransmitter metabolites for biomarker discovery in Mucolipidosis IV
Awardee: Yulia Grishchuk
Institution: MGH
Grant Amount: $64,335
Funding Period: February 1, 2022 - January 31, 2023
Summary:
Mucolipidosis IV (MLIV) is an ultra-rare lysosomal disorder resulting from inactivating mutations in the MCOLN1, the gene encoding the lysosomal cation channel TRPML1. Patients typically present in the first year of life with delayed developmental milestones and reach a plateau in function roughly equivalent to the 18-20 month-old level. In contrast to other lysosomal disorders, patients with MLIV exhibit a relatively stable clinical course before early adolescence with neurological deterioration first emerging after puberty. Recently, we reported a novel TRPML1 gene replacement strategy that restored motor function when administered to either presymptomatic, newborn MLIV mice or symptomatic mice at 2 months of age. Excitingly, these data suggest that TRPML1 gene therapy may be able to restore motor development in patients with MLIV rather than simply delaying disease progression. However, the time needed for restored developmental processes to produce a clinically meaningful improvement in function in humans is uncertain and will likely exceed the 1 year time period in which traditional FDA approved trials require demonstration of efficacy. As such, there is now a critical unmet need for a clinically tractable biomarker to measure TRPML1 activity restoration in the brain. The goal of this proposed study is to determine whether loss of TRPML1 activity alters neurotransmitter metabolite levels in humans and mice with mucolipidosis IV, aiming to develop a therapeutic biomarker for AAV based gene replacement therapy.