Our Gen.1 compound screen was performed with a library of 8,174 unique drug-like small molecules (Gen.1 library) assembled using criteria on the quality and depth of their target, MoA, in vitro, in vivo, and clinical annotation data. We tested these compounds in an average of 3 biologic replicates (primary cells from different animals, actual range N = 2 – 4). We identified 189 ‘Hits’; compounds that decrease the phenotypic age with a P_adj < 0.01.

We use the ranking from the confirmation testing to select molecules to move into the in vivo phase of screening. In the in vivo phase of screening. We utilize a mouse model of progeria syndrome to test our “Hit” molecules for therapeutic effects against the development of age-associated diseases. In this mouse model, animals are healthy until about 6 weeks of age when they start to develop many symptoms, pathologies, and conditions of aging. By 15 weeks of age, these animals display moderate to severe pathology. We start dosing the animals in the asymptomatic stage and monitor the progression of disease development using many vital, functional, and physiologic measurements. Additional detailed phenotypic analysis is conducted after the completion of chronic dosing.

FTX005778 Promotes beneficial lipid storage.

Starting at 6 weeks of age, progeria animals develop startling lipodystrophy and lipoatrophy, which can be monitored in the live phase of dosing by performing TD-NMR-based body composition analyses. We found that animals dosed orally with FTX005778 displayed significant preservation of body fat compared to the decline experienced by animals dosed with vehicle. FTX005778 induced a modest increase in body fat that was stable over the course of dosing in male progeria animals and delayed the decline in body fat in female animals.

Subsequent analyses found that animals dosed with FTX005778 had a profound increase in intrascapular brown adipose tissue mass. Brown adipose tissue is a highly metabolic adipose tissue that is central to metabolic and thermogenic homeostasis. It is well established that brown adipose mass positively correlates with ‘healthy’ metabolic states and declines with age. At 15 weeks of age, the brown adipose tissue in progeria animals dosed with vehicle was atrophied and almost completely devoid of lipid. However, the brown adipose tissue of 15-week old animals dosed with FTX005778 is 2-3 times the mass of vehicle treated and histologically appear normal/healthy: it is comprised of large multilocular adipocytes.