Target Validation of Splicing Repression, a Major Function of TDP-43 in the Motor Neuron

Unmet Need
Amyotrophic lateral sclerosis (ALS) is a rare but debilitating disease characterized by the death of motor neurons that eventually leads to difficulty moving, speaking, swallowing, and breathing. The fundamental cause of ALS is unknown and as a result treatment options are primarily restricted to physical therapy to help prolong muscle strength. In the last decade the TDP-43 protein, which prevents abnormal RNA splicing from occurring, has been identified as having a central role in the pathogenicity of 97% of ALS cases. An understanding of how TDP-43 causes ALS is essential to the development of efficacious therapeutics.
 
Technology Overview
Researchers at Johns Hopkins University have identified a novel approach to treating ALS by restoring TDP-43 activity in the nucleus and preventing abnormal RNA splicing. This approach was identified by inducing ALS symptoms in mice and flies by removing TDP-43 in motor neurons using Cre-Lox recombination technology. ALS symptoms were abrogated in these models by using adeno-associated virus to express a novel gene construct consisting of TDP-43 RNA binding domain fused to a general repressor of RNA splicing. Further development of this technology may lead to a gene therapy for the treatment of ALS.
 
Stage of Development
Data from preclinical animal models is available.
 
Publications
Manuscript in preparation.
 

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