IL-34: A Potential Therapeutic Target for Dysferlinopathy

Vicki Rubin Kelley, PhD

Brigham and Women's Hospital/Harvard Medical School

Dr. Kelley is a Professor of Medicine at Harvard Medical School and Brigham and Women's Hospital (Boston, MA).

Research Projects

Past Projects

Objective: To determine whether IL-34 is a promising therapeutic target and predictive for dysferlinopathy.

Macrophages (Mø) are prominent in the inflamed skeletal muscles of patients with dysferlinopathy. Mø are integral to both tissue repair and destruction. Injured skeletal muscle recruits inflammatory, cyto-destructive Mø that transition over time into reparative/regulatory Mø to regenerate and heal. As muscles in patients with dysferlinopathy do not heal, cyto-destructive Mø are likely central to non-resolving inflammation resulting in the loss of muscle fibers. IL-34 and CSF-1 are the principle cytokines that promote Mø survival and proliferation. Thus, IL-34 and/or CSF-1 are prime candidates responsible for increasing Mø and thereby promoting non-resolving inflammation, failed repair and dysferlinopathy.

Our preliminary data in dysferlin (Dyst)-deficient (BLA/J) mice indicates that: (i) inflammatory cyto-destructive Mø are abundant in inflamed muscles, adjacent to damaged myofibers; (ii) adoptively transferred bone marrow derived Mø are continuously recruited to and proliferate within muscles with rapidly advancing pathology; (iii) adoptively transferred bone marrow Mø skew towards a cyto-destructive phenotype in muscles with dysferlinopathy; (iv) intra-muscle CSF-1 and IL-34 increase along with the rise in numbers of Mø accumulating in BLA/J muscles and (v) IL-34, not CSF-1, increases in patients with dysferlinopathy compared to healthy controls.  Fueled by this evidence, we will test the hypothesis that IL-34 mediates Mø driven dysferlinopathy. Effective treatments for dysferlinopathy do not exist. Our ultimate goal is use pre-clinical studies to seed clinical trials to determine whether blocking IL-34 suppresses dysferlinopathy in patients.