The Nature publication entitled "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport" reported that C9orf72, the most common cause of familial and sporadic ALS and Frontotemporal Degeneration, results in problems with nuclear protein trafficking that affect neural function and survival. The mutation causes the affected cells to create long strands of repeating RNA, thus blocking critical pathways for nuclear transport of proteins. A first set of experiments using a fruit fly model of human ALS to screen for candidates that block brain cell death in a living organism identified a protein RanGAP, a key regulator of nucleocytoplasmic transport, that acts as a potent suppressor of neurodegeneration. Consistent with the interaction of RanGAP with XPO1 (exportin 1), the studies further showed that suppressing nuclear export of proteins also suppresses neurodegeneration. The results were validated in human stem cell derived motor neurons and autopsied brains.
In a second set of experiments, using fly and human stem cells, the addition of antisense oligonucleotides targeting C9orf72 or small molecule inhibitors of XPO1 including one of Karyopharm's SINE™ compounds, restored proper protein nuclear localization. Importantly, this effect was sufficient to suppress neurodegeneration. This study supports the premise that nucleocytoplasmic transport defects may be a fundamental pathway for ALS that is amenable to pharmacotherapeutic intervention. The results from this publication will also be presented at the
"This valuable research reinforces that modulation of nucleocytoplasmic transport presents a potential therapeutic strategy for neurodegenerative diseases such as ALS," said
In addition to the above presentation, Karyopharm's other collaborators will be presenting abstracts on the neuroprotective effects of SINE™ compounds at two upcoming neuroscience meetings this fall. Sami Barmada, MD, Ph.D. from the
Karyopharm's SINE compound research efforts in ALS are being supported entirely by collaborator grant funding. The ALS Therapy Alliance is funding the in vitro research of Karyopharm's collaborator
About Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. The degeneration of nerve cells eventually causes people with ALS to lose the ability to initiate and control muscle movement. There is no cure for the disease and few treatment options exist. Approximately 6,400 new cases of ALS are diagnosed each year in the United States. ALS usually strikes between the ages of 40 and 70 with death occurring within three-to-five years from diagnosis. Death is usually due to respiratory failure because of diminished strength in the skeletal muscles responsible for breathing. ALS affects approximately 400,000 people worldwide, with approximately 30,000 in
KPT-350 is Karyopharm's orally active, brain penetrant, anti-inflammatory SINE™ XPO1 antagonist. It is an analog of SINE™ compound selinexor (KPT-330), which is being developed for the treatment of cancer. KPT-350 has been evaluated in preclinical studies in traumatic brain injury (TBI). In animal studies, the gross size of lesions resulting from TBI were dramatically reduced in rats treated with KPT-350. Furthermore, the KPT-350-induced protection at the site of the injury resulted in healthy adjacent tissue with viable neurons, which appears to indicate that KPT-350 exerted a neuroprotective effect to prevent permanent neuronal loss due to the blunt force injury. Karyopharm is evaluating SINE™ compounds, including KPT-350, in additional inflammatory, neuroprotection and autoimmune models including multiple sclerosis, ALS, TBI and systemic lupus erythematosus.
Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases. Karyopharm's SINE™ compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent activity against a variety of different human cancers, SINE™ compounds have also shown biological activity in models of cancer, inflammation, autoimmune disease, certain viruses, and wound-healing. Karyopharm was founded by Dr. Sharon Shacham and is located in
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the therapeutic potential of and potential clinical development plans for Karyopharm's drug candidates, including the timing of initiation of certain trials and of the reporting of data from such trials. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the company's current expectations. For example, there can be no guarantee that any of Karyopharm's SINE™ compounds, including KPT-350 or selinexor (KPT-330), or any other drug candidate that Karyopharm is developing will successfully complete necessary preclinical and clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the
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Source: Karyopharm Therapeutics
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