Small Molecule Drug Discovery for CLN3 and CLN6 Disease

项目总结/文摘

PROJECT SUMMARY/ABSTRACT CLN3 and CLN6 disease are subtypes of a wider family of pediatric neurodegenerative diseases called the Neuronal Ceroid Lipofuscinoses (NCLs) or Batten Disease. The NCLs affect approximately 6-8 children per 100,000 live births worldwide. Common symptoms of CLN3 and CLN6 disease include vision impairment which progresses to blindness, seizures which increase in severity, cognitive and motor decline progressing to dementia, and ultimately premature death. No cure or effective treatment for either CLN3 or CLN6 disease is known. The development of new disease-modifying agents to treat CLN3 and CLN6 disease is an urgent and unmet medical need. Common phenotypes that are shared between all NCLs include dysfunctional autophagy leading to accumulation of storage material, reduced expression of the anti-apoptotic protein Bcl-2 and increased ceramide production leading to apoptotic death of neurons, and dysfunctional mitochondria. Autophagy and apoptosis are physiological process that contribute to cellular homeostasis. Dysfunction of one, or in many cases, both processes, is phenotypic across many neurodegenerative diseases in addition to the NCLs. While targeting either process individually results in promising pharmacological effect, no small molecule has been identified that is capable of modulating both synergistically. While a multi-target approach has been used in cancer treatment for many years, it has only recently begun being applied to neurodegenerative diseases and has yet to be explored in CLN3 and CLN6 disease. Through a structure-based approach, we have identified a library of multi-functional compounds that fuse autophagy activation activity, anti-apoptotic Bcl-2 induction and decreased ceramide synthesis resulting in translational activity to protect human induced pluripotent stem cell (iPSC)-derived neurons from externally- induced and phenotype-induced apoptosis. Moreover, we have shown in our preliminary data that iPSCs obtained from CLN3 patients and derived to functional neurons recapitulate the aberrant autophagy, apoptosis and mitochondrial function phenotype of the disease, and that these phenotypes can be rescued by selected lead compounds. Further, we show proof-of-concept that our lead compounds rescue CLN3 disease phenotypic behavioral deficits in a transgenic CLN3 mouse model. The goal of this application is to optimize our proprietary library of neuroprotective compounds to further understand their minimum pharmacophore, confer ‘drug-like’ properties, identify and eliminate any potential toxicity, optimize drug metabolism and pharmacokinetic parameters, further credential their mechanism of action and demonstrate proof-of-concept protective activity in additional patient iPSC-derived neuron lines and CLN3 and CLN6 transgenic mice.