Preclinic dose and delivery regime optimization and long-term efficacy evaluation of ribitol treatment for FKRP related dystroglycanopathy

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Program Director/Principal Investigator (Last, First, Middle): Lu Qi Long Project Summary Mutations in FKRP gene cause muscular dystrophy with wide variation in severity with characteristic biochemical feature of defect in glycosylation of -DG. The progressive nature of the disease leads to a continuous loss of muscle fibers and increase in fibrosis, and finally loss of muscle function and ultimately failure of respiratory and cardiac functions, leading to early death. Currently no treatment is available although several experimental therapies are being tested in animal models. Recently, FKRP has been identified as a ribitol-5-phosphate transferase using CDP-ribitol as the substrate for the extension of the laminin binding biglycan (matriglycan) on -DG, a critical step for muscle integrity. Earlier study suggests that ribitol supplement can lead to an increase of CDP-ribitol levels in cells. We also demonstrated recently that mutant FKRPs retain sufficient levels of function to glycosylate -DG by AAV mediated gene therapy with mutant P448L FKRP as the transgene. We have now demonstrated that supplement of ribitol increases levels of matriglycan in our clinically relevant P448L mutant mouse model, resulting in significant improvement in muscle pathology and functions in both cardiac and skeletal muscles. This opens a novel, highly specific and clinically applicable means to treat the majority of FKRP muscular dystrophy. In this proposal, we will first optimize dosage and administration regime of ribitol in fkrp P448L mutant mouse model by testing a range of doses with both routes of gavage administration and in drinking water. The effects will be evaluated by levels of functional glycosylation and improvement of dystrophic pathology. We will then examine long-term efficacy (12 months) and safety of the selected dosing and delivery regime of ribitol in three strains of FKRP mutant mice, P448L, L276I homozygote, and P448L/L276I compound heterozygotes bearing clinically relevant mutations in more than 90% patients and representing diseases from mild to severe dystrophic phenotypes. These mutant strains have been established in the McColl Lockwood Laboratory. The aim is to establish at least one dose and delivery regime with long-term efficacy for further development towards clinic trials. The goal of this proposal is to establish a practically deliverable dosing and treatment regime with long- term therapeutic efficacy in clinically relevant mouse models for IND application. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page