Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative universal fatal disease for which there is no cure. Although viewed as a rare disease by pharmaceutical companies, the financial and emotional costs for ALS patients and their families are immeasurable. With only two FDA-approved drugs available to treat ALS it is imperative that new approaches are being sought after. We are a team of four investigators with complementary expertise that have been working together to tackle ALS from a fresh perspective and in a comprehensive manner. The goal of our studies is to focus on an unconventional target, the RNA binding protein TDP-43, which has emerged as a common denominator across ALS patients due to its association with clinical pathology in 97% of patients, regardless of etiology. Therefore, if successful, our approach is likely to serve the majority of the patient population, whether the disease is associated with a family history of ALS (fALS) or with sporadically occurring ALS (sALS).

Our approach and choice of TDP-43 as a target are based on its known function as an RNA binding protein and on published data from our group and others in the field showing that RNA sequestration is a key pathological event in ALS. We have identified RNA targets that when sequestered by TDP-43 are not translated into protein at appropriate levels and in the right place. The lack of these proteins is thought to affect the viability of motor neurons, which are known to degenerate during ALS disease progression. We therefore hypothesize that an inhibition of this RNA sequestration using small molecule compounds will provide neuroprotection during disease progression and therefore improve patients' lives.

Our team represents expertise in small molecule design, synthesis, and development, as well as RNA biology and mechanisms of ALS disease pathogenesis. We will generate and test novel small molecule compounds that interfere with TDP-43 and RNA binding such that the sequestered RNA will be released and can be translated into a functional protein again. We will use state-of-the-art biophysical and chemical tools for compound design and synthesis in combination with established and validated ALS disease models (fly and human cells). As a result, novel compounds will provide proof of principle that remodeling TDP-43/RNA complexes offers promising avenues for therapeutic development for ALS and other diseases characterized by TDP-43 pathology, including Frontotemporal Dementia (FTD).

Lead compounds arising from this drug development effort will be subjected to further preclinical development to qualify for investigational new drug (IND) applications with the involvement of the pharmaceutical industry, the NINDS translational mechanisms, the Blueprint Neurotherapeutics Network, or other translational programs.

Impact: Our studies will provide a starting point towards the development of novel therapeutics for ALS by targeting TDP-43. Positive outcomes of these studies would enable rapid implementation that could lead to effective preclinical leads for ALS therapies. We have established a unique partnership between the PIs, a molecular/cell biologist, a structural biologist, a medicinal chemist, and a stem cell biologist working with patient-derived samples. These studies are consistent with the FY17 goal of Funding innovative preclinical research to promote the development of new treatments that may contribute to a cure for ALS.