Neurosteroids, synthesized from cholesterol in the nervous system, affect growth and differentiation of neurons. The lead collaborators showed that post-embryonic neurosteroid synthesis is altered in a time- and region-specific fashion in the BALB/c Niemann-Pick C mouse, and that neurons and glia expressing steroidogenic enzymes are lost. In particular, the synthesis of the GABA-ergic neurosteroid allopregnanolone (ALLO) is substantially diminished at birth, when the rodent brain is still undergoing maturation and decreases further over time. It was demonstrated that appropriately timed treatment of NPC mice with ALLO increases the lifespan of these mice and delays the onset of neurological impairments that are hallmarks of this disease in mice tremor, ataxia, and hindlimb dysfunction. Furthermore, ALLO treatment of NPC mice significantly increases cerebellar Purkinje and granule cell survival and substantially reduces accumulation of cortical gangliosides GM1, GM2 and GM3. The BrIDGs team completed the following activities for the development of ALLO: - Formulation development - Manufacture of GMP drug product - Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies - Investigational New Drug (IND)-directed toxicology As a result of BrIDGs support, the lead collaborator was able to file an IND application, which was cleared by the Food and Drug Administration (FDA). BrIDGs support is completed and the collaboration on this project is now concluded.
