NBD Therapy for Duchenne Muscular Dystrophy

Dr Denis Guttridge
Ohio State University

22nd January 2014

The TACT application submitted by Dr Denis Guttridge proposes to use a Nemo binding domain (NBD) peptide coupled to a cell penetrating peptide as a blocker of the NF-κB pathway to treat Duchenne muscular dystrophy (DMD). The NF-κB pathway is strongly implicated in the pathogenesis of DMD. In macrophages, NF-κB promotes inflammation and fiber necrosis, while its activation in damaged muscles inhibits muscle stem cell regeneration. Thus targeting NF-κB should both dampen the immune response and boost new muscle growth. The NBD peptide is a specific blocker of the NF-κB pathway which acts as a competitive inhibitor to block the association of the IKK complex whose kinase activity acts directly upstream to stimulate NF-κB. The applicant has published data showing that NBD treatment leads to a reduction in inflammation and decreased pathology in two mouse models and has similar unpublished data in a dog model of DMD.

TACT was enthusiastic about the targeting of the NF-κB pathway as a potential therapy for all DMD patients. TACT provided advice on the feasibility of using muscle biopsies to assess treatment effect, the use of non-invasive biomarkers, biodistribution and pharmacokinetic issues, patient burden associated with the proposed treatment schedule, assessment of interaction with corticosteroids and the potential for immunogenicity.

12 Apr 2017