Development of Neurosteroids for Lysosomal Storage Disorders

Niemann-Pick disease type C is a very rare inherited inability to metabolize cholesterol and other fats. Because of this inability, cholesterol accumulates in the liver and the spleen and other fats accumulate in the brain, causing progressive neurodegeneration. In most cases, neurological symptoms appear between the ages of 4 and 10 years, but the disease may not appear until a person is an adult. Progression is slower the later the symptoms appear, but Niemann-Pick C is always fatal. The majority of children with the disease die before the age of 20. No treatment is known. The researchers are developing a therapy for children with Niemann-Pick C based on a neurosteroid, a hormone that acts on the growth and differentiation of brain cells and is produced in the nervous tissue. The drug has shown activity in both increasing brain cell survival and reducing the accumulation of fats in the brain that causes the brain degeneration.

Scientific Synopsis

Niemann-Pick disease type C is a fatal, autosomal recessive, childhood-onset neurodegenerative disorder for which there is no treatment. It is a lysosomal lipid storage disease characterized by defective trafficking of intracellular cholesterol and lysosomal accumulation of unesterified cholesterol, gangliosides and other lipids. Neurosteroids, synthesized from cholesterol in the nervous system, affect growth and differentiation of neurons. We 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 the Niemann-Pick C mouse. 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.

Our data show that appropriately timed treatment of Niemann-Pick C 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 Niemann-Pick C mice significantly increases cerebellar Purkinje and granule cell survival and substantially reduces accumulation of cortical gangliosides GM1, GM2 and GM3. Our recent data indicate that this treatment is not limited to Niemann-Pick C, as two other lysosomal storage disorders are treated effectively with ALLO. To obtain data necessary for submission of an Investigational New Drug (IND) application to the FDA to treat children with Niemann-Pick C with ALLO, we have established the pharmacokinetics and pharmacodynamics of ALLO in neonatal, juvenile and adult wild-type and Niemann-Pick C mice and optimized ALLO treatment in Niemann-Pick C mice. Submission of our pre-IND document and type B meeting with the FDA has provided direction for our safety and toxicology studies in animals and in vitro, needed for IND submission.

We are requesting program support to complete these safety and toxicity studies and for preparation of GMP allopregnanolone for use in these studies and in phase I clinical trials. The use of neuroactive steroids in the treatment of degenerative brain diseases has not been described previously. We believe that other brain diseases, including but not limited to congenital storage diseases, may benefit from similar treatments with neuroactive steroids. Thus, this proposal is directed toward obtaining preclinical safety and toxicity data necessary to file an IND for the treatment of a broad group of disorders with a novel class of drugs, with Niemann-Pick C as the model disease.

Lead Collaborator

University of California, San Francisco
Synthia Mellon, Ph.D.

Public Health Impact

The allopregnanolone treatment that we have developed in mouse models of Niemann-Pick disease type C also shows significant benefits in two unrelated mouse models of human lysosomal storage disorders, Sandhoff disease and Sanfilippo disease. Currently, there are no treatments for any of these three lysosomal storage disorders, and thus allopregnanolone treatment represents a major advance in treatment of three different orphan diseases.


As a result of BrIDGs support, the lead collaborator was able to file an IND application in December 2017, which was cleared by the Food and Drug Administration. BrIDGs support is completed and the collaboration on this project is now concluded.

Project Details

  • Formulation development
  • Manufacture of GMP drug product
  • Pharmacokinetic studies
  • IND-directed toxicology