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Nuclear blockade unlocked

How restoring nuclear transport function in motor neurons could treat ALS

Understanding the basic biology of amyotrophic lateral sclerosis (ALS) is still the biggest barrier to a serious breakthrough in the disease, despite the fact that genetic studies have pointed to some clear culprits for a significant percentage of cases. Now, studies from three separate groups reveal that mutations in C9orf72 - one of the most commonly affected genes - disrupt nuclear transport, and the mechanism uncovered could lead to a new class of therapies that improve the outlook not only for ALS but also for other neurodegenerative diseases.

The papers, two in Nature and one in Nature Neuroscience by groups from The Johns Hopkins University, St. Jude Children's Research Hospital and Stanford University, demonstrated that the mutations in C9orf72 impair the normal transport of proteins and RNA into and out of the nucleus in motor neurons, the cells most affected by ALS, leading to neurotoxicity.

At least one company has already taken notice of the data. Just a week after the papers were published, cancer company Karyopharm Therapeutics Inc. announced plans to test KTP-350, one of its nuclear transport-targeting compounds, in preclinical models of ALS. According to Margaret Lee, VP of product leadership and biology at Karyopharm, the company has been exploring its XPO1 inhibitors, which block nuclear export, in neurodegenerative diseases such as multiple sclerosis (MS) and ALS, and the new studies support Karyopharm's preclinical work.

"It is a really exciting time for the field of neurodegeneration to have the opportunity to prosecute

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