Therapeutic Effect of KPT-350 in a Preclinical Model of Duchenne Muscular Dystrophy (S42.003)

Objective: This study evaluated the effectiveness of the Selective Inhibitor of Nuclear Export (SINE) compound KPT-350 in a zebrafish model of Duchenne muscular dystrophy (DMD).

Background: DMD is an X-linked disorder that afflicts approximately 1:5000 live male births, making it the most common form of muscular dystrophy worldwide. The nuclear export protein XPO1/CRM1 is a promising target for the treatment of neurological disorders with inflammatory pathology such as DMD. IκBα, a protein cargo of XPO1, inhibits pro-inflammatory transcription factor NF-κB activity by preventing its transcription. KPT-350 is a potent, orally available, slowly reversible, small molecule inhibitor of XPO1, and KPT-350 administration increases the amount of endogenous I_KB, thus inhibiting NF_KB’s function.

Design/Methods: In order to assess the short term effect of KPT-350 treatment on dystrophic disease phenotype and muscle architecture, sapje zebrafish (a severe model of DMD) embryos were treated from 1 to 5 days post-fertilization (dpf) with vehicle, 1.25 μM KPT-350, 2.5 μM KPT-350, or 2.5 μM aminophylline (positive control). In order to assess the effects of long-term KPT-350 treatment on survivability, sapje zebrafish were treated 3x/week for 24 hrs/dose with vehicle, 0.1 μM KPT-350, 1.0 μM KPT-350, or 2.5 μM aminophylline for 21 dpf.

Results: In short-term treatment studies, KPT-350-treated sapje zebrafish showed significant prevention of the muscle degeneration pathology associated with dystrophin deficiency and improved overall muscle architecture as determined by histological analysis of myosin heavy chains. With long term treatment, KPT-350 extended the lifespan of the sapje zebrafish, with a significant number of KPT-350-treated sapje mutants surviving well past 10 dpf, and reduced overall dystrophic pathology.

Conclusions: KPT-350 is an IND-ready compound and our studies demonstrate that it can improve the symptoms associated with muscular dystrophy and is a promising small molecule compound for the treatment of dystrophin-deficiency.

Study Supported by: Karyopharm Therapeutics

Disclosure: Dr. Gibbs has nothing to disclose. Dr. Hightower has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Spinazzola has nothing to disclose. Dr. Mead has nothing to disclose. Dr. Widrick has nothing to disclose. Dr. Tamir has received personal compensation for activities with Karyopharm Therapeutics Inc., as an employee. Dr. Cochran has received personal compensation for activities with Karyopharm Therapeutics Inc. as an employee. Dr. Landesman has received personal compensation for activities with Karyopharm as an employee. Dr. Kunkel has received personal compensation for activities with Summit, Sarepta, and Clartitas as an advisory board member and consultant. Dr. Kunkel has received research support from Pfizer. Dr. Alexander has nothing to disclose.