In Vivo Gene Targeting to Treat Inherited Bone Disease

Project: Research project

Description

? DESCRIPTION (provided by applicant): Mutations in bone stem cells can impair bone metabolism and regeneration. Osteogenesis imperfect (OI) is the most common form of genetic bone disease and characterized by bone fragility with clinical manifestations varying from a mild increase in fractures to severe bone deformities and death. Individuals with OI have mutations that alter procollagen structure or production and lead to abnormal collagen fibril formation disrupting bone development and renewal. Treatment options for OI are limited and do not alleviate the complications seen in OI. Our recent work has demonstrated that AAV gene targeting vectors can disrupt the mutant collagen alleles that cause OI and that targeted cells produced normal collagen and formed bone. While these results indicate the effectiveness of genomic editing with targeting frequencies approaching 1%, an enhancement of AAV gene targeting is required to provide more robust in vivo genetic manipulations. Here we will expand upon our successes and propose three lines of investigations to develop a therapeutic approach for patients with inherited bone disease. First we will modify collagen genes using a CRISPR-AAV system that will allow for the disruption or correction of genes that cause OI in vivo. Second, we will investigate whether genetically corrected bone stem cells have a growth advantage in vivo and how TGF-beta signaling affects the extra-skeletal manifestations of bone disease. Finally we will conduct a series of experiments in a preclinical rabbit model to establish
the optimal gene targeting delivery protocol. Successful completion of this proposal will lead to an improved understand of TGF-beta signaling and stem cell kinetics in bone and advance AAV gene targeting toward a clinical trial.
StatusActive
Effective start/end date7/1/156/30/20

Funding

  • National Institutes of Health: $349,800.00

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Gene Targeting
Bone Diseases
Osteogenesis
Bone and Bones
Collagen
Stem Cells
Transforming Growth Factor beta
Clustered Regularly Interspaced Short Palindromic Repeats
Procollagen
Mutation
Inborn Genetic Diseases
Bone Regeneration
Bone Development
Genes
Alleles
Clinical Trials
Rabbits
Therapeutics
Growth

ASJC

  • Medicine(all)