Advisor(s)

Matthew Alexander

Committee Member(s)

Anna Thalacker-Mercer
Jeremy Herskowitz
John Parant
Rosa Serra

Document Type

Dissertation

Date of Award

6-1-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Cell Biology

Abstract

Duchenne muscular dystrophy (DMD) is a progressive, x-linked neuromuscular disorder affecting 1/5000 male births every year. DMD results from mutations in DMD, a critical structural protein within the muscle. In the absence of Dystrophin, the muscle degrades, increasing inflammation, destabilizing the cell membrane and going through constant cycles of regeneration which depletes the stem cell population. Over time, muscle tissue is replaced by fibrosis and adipose tissue, leading to loss of ambulation, respiratory and cardiac failure leading to death by early 20s. The standard of care for DMD patients is corticosteroid treatment. However, gene therapies have recently emerged which present significant improvements in patient outcomes, but are not wholly effective and not applicable to all patients. The need for co-treatments and alternative therapeutic targets remains. Two potential therapeutic strategies have been evaluated in this thesis. KPT-8602 is a selective inhibitor of nuclear export (SINE) compound. KPT-8602 functions by binding XPO1 and limiting the nuclear export of inflammatory transcripts, particularly targeting the nf-Κb pathway, known to drive inflammatory pathology in DMD. We show that regular oral treatment with KPT-8602 improved muscle function, decreased immune cell recruitment, and decreased osteopontin levels in the skeletal muscle. Overall, this data indicates that SINE compounds are a viable co-treatment strategy in DMD. Additionally, we investigated a member of the Dedicator of Cytokinesis (DOCK) family of proteins, DOCK7. We show that human loss of function mutations in DOCK7 result in epileptic encephalopathy, hypotonia, and ataxia. These typically present as recessive, bi-allelic mutations and are ultra rare. We then investigated the tissue-specific role of Dock7 using the cre-lox system to generate conditional mouse models. The Dock7 mKO model uses the human skeletal actin promoter to drive cre expression in skeletal muscle fibers while the Dock7 vKO model uses the acetylcholinesterase promotor to drive cre expression in motor neurons. Using these models we demonstrate that Dock7 ablation leads to reduced muscle function, aberrant fiber sizes dysregulation of Wnt signaling, and disorganized neuromuscular junctions. We also used these models to generate a Dock7 haploinsufficiency in mdx5cv mice restoring Dock7 to WT levels and improving hallmarks of dystrophic pathology.

Keywords

DMD;Dock7;Duchenne muscular dystrophy;KPT-8602;modifier;muscle biology

Download

Share

COinS