Modulation of Heat Shock Protein B8 by Colchicine: A Promising Therapy for an Inclusion Body Myopathy


Non-Gene Targeting Therapies

Poster Number: 128


Lan Weiss, MD, PhD, Lac Ta, BSc, Alyaa Shmara, Rebekah Wei, Eshanee Mohanty, Cheng Cheng, PhD, Virginia Kimonis, MD


1. University of California, Irvine, 2. University of California, Irvine, 3. University of California, Irvine, 4. University of California, Irvine, 5. University of California, Irvine, 6. University of California, Irvine, 7. University of California, Irvine

Heat shock protein family B member 8 (HSPB8) is a chaperone involved in the Chaperone Assisted Selective Autophagy (CASA) complex. HSPB8 in conjunction with BAG3 recognizes and promotes the autophagy-mediated removal of misfolded proteins associated with motoneurone disease, Alzheimer, Parkinson, Huntington, and spinocerebellar Ataxia 3. Mutations in HSPB8 gene, which has previously been associated with the axonal type of Charcot Marie Tooth, has recently been associated with autosomal dominant Rimmed Vacuolar Myopathy. Affected patients have proximal limb girdle and distal myopathy with muscle biopsy showing fatty replacement, endomysial fibrosis, rimmed vacuoles, and muscle atrophy and early demise. There is no treatment available for this debilitating disease. Our studies showed that patients with HSPB8 mutation have reduced expression of HSPB8 and disrupted TDP-43 and autophagy pathology in patient fibroblasts. A prior high throughput drug screening project in neuronal cells indicated that colchicine was one of the top drugs that significantly increased HSPB8 expression. We hypothesize that enhancing HSPB8 expression by colchicine could rescue the myopathy phenotype. A dose-response analysis (0.1, 0.5 and 1 uM) was carried out to evaluate the optimal concentration of on HSPB8 patient and age and sex matched control fibroblasts. We observed that colchicine increased expression levels of HSPB8 and also co-chaperone BAG3 at the lowest concentration, 0.1nM of Colchicine. We aim to treat our newly created c.515dupC Hspb8 knockin mouse model with colchicine in the hope of translating these findings to a novel treatment for patients. Results from this application could also help develop treatment strategies in related neuromuscular disorders.