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Aug 17

The ALS Association and Teva Grant Two Awards to Packard Center researchers as part of the Teva CNS Target Identification Crowdsourcing Challenge

Packard Center News
The two awards will be granted to Philip C. Wong, Ph.D., and to Jonathan C. Grima, Ph.D., and Jeffrey D. Rothstein, M.D., Ph.D., all from Johns Hopkins University School of Medicine in Baltimore, Maryland.

The ALS Association and Teva Pharmaceutical Industries Ltd. (“Teva”) announced today the recipients of the Teva CNS Target Identification Crowdsourcing Challengeawards for their outstanding proposals on novel ALS targets. The two awards will be granted to Philip C. Wong, Ph.D., and to Jonathan C. Grima, Ph.D., and Jeffrey D. Rothstein, M.D., Ph.D., all from Johns Hopkins University School of Medicine in Baltimore, Maryland.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to death of neurons in the brain and spinal cord. There are only two drugs approved in the United States for treating ALS with limited effects, and new therapies that substantially prolong lifespan are urgently needed. An essential step toward developing new treatment avenues is to unravel the biological processes that go awry in this disorder and identify novel molecular targets for drug intervention.

To address the severe, unmet need for new therapies for disorders of the central nervous system, The ALS Association, the Huntington’s Disease Society of America (HDSA), and Teva launched The Teva CNS Target Identification Crowdsourcing Challenge to seek novel targets with therapeutic potential for treating neurodegenerative disease, pain, and migraine. The Challenge was launched in collaboration with InnoCentive, a global pioneer in innovation and crowdsourcing.

Two teams were selected by Teva and The ALS Association to each receive $10,000 for proposals of ALS targets that had been recently implicated in disease pathophysiology, and which were viewed as particularly interesting for exploration as therapeutic targets:

  • Philip C. Wong, Ph.D., of Johns Hopkins University School of Medicine: TDP-43 dependent splicing repression as a mechanism-based therapeutic target for ALS.
    • TDP-43 is an RNA binding protein that is found in neuronal cytoplasmic aggregates in more than 95 percent of ALS cases and is mutated in approximately 4 percent of familial ALS patients. Dr. Wong’s group has identified a role for TDP-43 in repressing splicing of cryptic exons – genomic regions flanked by splice sites, which are not normally incorporated into the protein coding mRNA (Ling et al., 2015). Loss of function of TDP-43 causes these cryptic exons to be included in the mRNA and disrupt expression of many proteins. Restoring this function of TDP-43 ameliorated the motor and survival defects in fly and mouse models that mimic the depletion of nuclear TDP-43 occurring in motor neurons of ALS patients.
  • Jonathan C. Grima, Ph.D., and Jeffrey D. Rothstein, M.D., Ph.D., of Johns Hopkins University School of Medicine: Targeting the nuclear pore in neurodegeneration.
    • Grima and Rothstein have previously proposed the Nuclear Pore Hypothesis of Neurodegeneration, and this has been the centerpiece of Grima’s graduate work at Johns Hopkins. This hypothesis explains that a defect in nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) function may in fact underlie the majority of neurodegenerative diseases, and what may distinguish one disease from another are the unique components of the NPC and NCT machinery that are affected. Initial studies (Zhang et al., 2015) identified components of the NPC as genetics modifiers of neurodegeneration in the most common genetic cause of ALS. Additional work from Grima, Rothstein, and others has demonstrated for the first time that defects in this pathway may extend beyond ALS to include other neurodegenerative diseases, such as Huntington’s disease (Grima et al., 2017) and Alzheimer’s disease (Eftekharzadeh et al., 2018). This proposal focused on targeting several of these key NPC proteins.

“This is a particularly exciting time in drug development for ALS, with many novel therapeutic approaches under investigation,” commented Lucie Bruijn, Ph.D., M.B.A., chief scientist for The ALS Association. “The ALS Association is pleased to recognize the two recipients of the Crowdsourcing Challenge, together with Teva, and look forward to the further development of these promising therapeutic targets.”

“We were enthusiastic about the level of interest in the program and number of submissions received,” said Steffen Nock, Ph.D., senior vice president, Specialty Research & Development, at Teva Global R&D. “We found several of the proposals to be particularly interesting for further investigation as therapeutic targets for ALS, and are glad to partner with The ALS Association in granting these prize awards.”

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