Date of Award

Spring 5-12-2018

Level of Access

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Robert Burgess

Second Committee Member

Wayne Frankel

Third Committee Member

Greg Cox

Additional Committee Members

Lucy Liaw

Dustin Updike

Abstract

Charcot-Marie-Tooth Disease (CMT) is a clinically and genetically heterogeneous collection of inherited peripheral neuropathies generally characterized by progressive muscle atrophy, weakness, and loss of sensation in the distal extremities. This inherited disorder, for which there is currently no curative treatment, is the most common inherited disease of the peripheral nervous system, affecting 1:2,500 individuals worldwide.

Clinically, CMT is broadly divided into demyelinating (type 1) and axonal (type 2) forms. Although the clinical presentation can vary greatly in severity and progression within individual patients. Genetically, over 1,000 mutations in over 80 loci in the human genome have been linked to specific subtypes of CMT, suggesting there are many cellular and molecular routes to neurodegeneration in CMT. Together, these factors conspire against a single effective therapy, for all subtypes of CMT, suggesting that personalized genetic approaches may represent a more efficacious therapeutic strategy.

One presumed basis for the phenotypic variability of CMT is the presence of genetic modifiers. Here, we have used mouse models of CMT to investigate genetic modifiers of neuropathy. We show that the phenotype of these CMT mouse models becomes more severe in the presence of either of two other mutations that cause “subclinical” changes at peripheral nodes. These results have implications for CMT genetic diagnosis and prognosis and suggest possible personalized treatment strategies.

Furthermore, the development of gene therapy has provided an effective strategy for treating Mendelian disorders, such as CMT, where disease is primarily caused by a single mutation. Personalized gene therapy approaches are being successfully deployed to treat recessive genetic disorders by restoring the expression of diseases, where treatment requires a reduction in expression of the mutated allele, has yet to be established. Here we use virally-delivered allele-specific RNAi to demonstrate the effectiveness of allele-specific silencing as a long-term treatment for dominantly-inherited forms of CMT. Importantly, this strategy will also have broad implications for other dominantly-inherited neuromuscular disorders.

Together, both studies clearly demonstrate how precision genetic approaches, either by targeting genetic modifiers or the disease allele itself may represent a more efficacious therapeutic strategy for individuals with CMT and others inherited neuromuscular disorders.

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