TDP-43 aggregation inhibitors for the treatment of ALS

Abstract Amyotrophic Lateral SclerosisALSis a universally fatal neurodegenerative disease that afflicts overout of everyindividualsProtein aggregation has been implicated as a primary driving force in ALS and multiple other neurodegenerative illnessesTDPis the principle component of the protein aggregates in ALSand TDPalso stands out as the only genetically defined ALS mutant gene that is also the hallmark pathology of sporadic ALSTDPis a RNA binding protein that is nuclear under basal conditions but translocates to the cytoplasm during stress where it forms RNA protein aggregate complexes termed andquot stress granulesandquotSGsDisease linked mutations in TDPenhance the ability of TDPto aggregate and form SGs in vitro and in animal modelsCytoplasmic TDPaggregates accumulate and also co localize with SGs in the spinal cord and brain of patients with ALSas well as in cellular and animal models of ALSThese integrated observations all point to a strong biological connection between TDPand pathogenesis of ALSAquinnah Pharmaceuticals licensedlead compounds that inhibit TDPand SG aggregation that were identified in a high throughput screen performed in the laboratory of DrBenjamin WolozinBoston University School of MedicineIn Phase I of SBIR fundingwe demonstrated the feasibility of targeting TDPwith these lead compounds for the treatment of ALSWe identified two oral bioavailable lead compounds that exhibit superb potencybrain pharmacokineticspenetration and half lifeand show improvement in TDPpathologic biomarkers in vitro and in vivo using a transgenic mouse model of TDPof ALSThis SBIR Phase II proposal presents a plan for the further preclinical development of a first in classnovelsmall molecule oral drug for the treatment of patients with ALSto slow and possibly reverse disease progressionFollowing success with our aimswe will advance to an Investigation New DrugINDapplication filing with the FDA and initiate Phase I clinical trials to provide promise to patients with ALS Project Narrative Amyotrophic Lateral SclerosisALSis a universally fatal disease for which there are currently no effective treatmentswhich means there is a dire need for novel therapeutic approaches in this fieldThis proposal aims to optimize new therapeutic compounds that prevent and reverse TDPaggregateswhich is the hallmark pathology found in andgtof patients in both sporadic and familial casesand to develop a lead drug candidate that can be tested in the clinic