Development of a novel oral brain penetrant therapeutic for ALS disease

PROJECT SUMMARY A diagnosis of Amyotrophic Lateral Sclerosis (ALS) is a death sentence. It affects motor neurons in the brain and spinal cord, leading to an inability to control muscle movement. Early symptoms include increasing muscle weakness of the arms and legs and difficulty in swallowing and breathing. As the disease advances, total voluntary muscle paralysis and death is observed in the most severely affected patients. The average life expectancy of a newly diagnosed ALS patient is approximately two to five years, and 80% of patients do not survive past five years. Currently there is no cure or effective treatment for slowing the progression of ALS. Motor neuron function is quickly impaired in ALS, leading to loss of voluntary muscle control throughout the body, serving as a key diagnostic parameter in patient classification. Treatments are predominantly palliative and include physical, occupational and speech therapy as well as medication to alleviate muscle cramps, fatigue, pain and sleep problems. Aquinnah Pharmaceuticals is developing an oral, brain penetrant, innovative new clinical drug candidate(s) designed to slow and potentially reverse the progression of ALS. Our approach has been to alter the most common pathological hallmark of ALS, the accumulation of insoluble, aggregated TDP- 43. In addition to being the key pathologic marker of ALS in the brain, TDP-43 appears to be central to disease because numerous genetic mutations in TDP-43 are also genetically linked and causal in patients with ALS. By reducing TDP-43 pathology and restoring its nuclear RNA splicing function, Aquinnah’s compound is expected to dramatically change the clinical outcome of this devastating disease in over 90% of all ALS patients (e.g. sporadic ALS). The Aims in this proposal encompass manufacturing, IND-enabling studies, and a pIND meeting with FDA. The novel therapeutic agent being developed in this proposal would represent the first effective disease-modifying therapy for the majority of patients with this devastating disease.