Some major accomplishments of SOAR-NPC, often in collaboration with other scientists, are summarized below:

Hydroxypropyl-beta-cyclodextrin (HPBCD); VTS-270

• Successfully obtained Bench-to-Bedside funding from the National Institutes of Health (NIH) to support pre-clinical HPBCD research. This proposal, which built upon the extensive work with HPBCD in SOAR-NPC labs, was the basis for the NIH/TRND NPC pilot project responsible for developing the Phase 1/2a clinical trial 
• Developed analytical assays for biomarkers and the first mass spectrometry-based assay for HPBCD, the latter of which has been implemented in the Janssen Pharmaceutical facility in Belgium. Together, these assays were instrumental in establishing dosing regimens in preclinical studies and monitoring therapy in the Phase 1/2a clinical trial.
• Provided guidance and support for biomarker development and continued preclinical studies on the HPBCD drug, VTS-270, for Vtesse, Inc. during the planning, launch, and execution of the Phase 2b/3 clinical trial.
• In conjunction with TRND, organized a meeting in September 2014 focused on HPBCD-induced hearing loss. In April 2016, SOAR-NPC hosted a follow-up meeting at Albert Einstein College of Medicine in Bronx, NY, to assess the status of potential compounds for mitigation of hearing loss caused by HPBCD and to update key scientists and clinicians in the field.

Vorinostat

• Awarded an NICHD U01 grant to support the Phase 1 clinical trial of Vorinostat in adult NPC patients.  This trial began in September 2014 and is now in the home stretch for completion of Phase 1.

Drug compound screening

• Tested >30 drug compounds in mice which contain an NPC mutation and exhibit many clinical and pathological aspects of NPC disease.
• In collaboration with the NIH, used high-throughput screening to evaluate 300,000 small molecules for the ability to increase levels and/or stabilize mutant NPC1 protein so that some can function in the cell. Lead compounds are currently being tested in NPC1 mouse models.

Animal models of NPC disease

• Generated a NPC1 mouse that contains one of the most common human NPC1 mutations, I1061T. Mice with this mutation are an ideal model to test therapies that upregulate NPC1 protein expression or stabilize mutant protein in order to increase the levels of functional protein [e.g., histone deacetylase (HDAC) inhibitors or small molecule chaperones].  This NPC1 I1061T mouse model has already been shared with three additional NPC investigators and is available to the NPC community, either directly from Dr. Daniel Ory or from a commercial source, Jackson Laboratories.
• Initiated work to generate another NPC1 mouse model, in order to study a mutation in some patients that is thought to result in later onset of the disease and a protracted disease progression.
• Continued to maintain and efficiently use a colony of NPC1 felines, the largest animal model of NPC disease, under the guidance of Dr. Charles Vite at University of Pennsylvania. The NPC1 cats were crucial to advancing hydroxypropyl-beta-cyclodextrin to clinical trial and continue to be a valuable asset in testing promising therapeutics, especially gene therapy at present.

Proteostasis

• Delved into the realm of proteostasis, or the area of cell biology comprised of making, folding, delivering, and degrading proteins within the cell.  Proteostasis is compromised in numerous diseases and NPC is no exception.  In studies using cultured cells, there is evidence that modulating the proteostatic network can reduce lipid accumulation, presumably by helping the mutated NPC1 protein become partially functional.
• In conjunction with the Ara Parseghian Medical Research Foundation, SOAR-NPC hosted an NPC-Proteostasis workshop at Washington University in St. Louis, bringing together leaders in the fields of proteostasis and NPC research. A direct outcome of this workshop was establishment of the NPC Virtual Proteostasis Network (NPC-VPN) and several new collaborations amongst attending scientists.  Four grants totaling $300,000 were funded with the goal of enhancing knowledge of the proteostatic network in NPC disease and generating data suitable to support NIH Program Project Grant submission on this topic. The Workshop has also resulted in two applications outside of SOAR.

Gene therapy for NPC1 disease 

• Initiated studies for gene therapy in the NPC1 cat model shortly after the clinical trial for hydroxylpropyl-beta-cyclodextrin got underway.  The gene therapy work in Dr. Vite’s laboratory is ongoing and a couple of recent publications using the Npc1 mouse model have demonstrated the potential of gene therapy as a treatment for NPC1 disease.  As a reminder, nearly 95% of NPC patients have a defect in the NPC1 gene, therefore, addressing the NPC1 defect first will provide benefit to the largest number of patients.

Biomarkers for NPC disease

• Identified oxysterols as an NPC disease biomarker and have developed a clinical test for oxysterols that is being implemented worldwide. This test replaces the more invasive and difficult filipin-staining assay as the diagnostic standard for NPC disease.
• Developed a prototype newborn screen for NPC based on discovery of novel plasma bile acid biomarkers. Current plans are to evaluate the assay in New York and Washington State. Assuming successful evaluation of the newborn screen, the goal will be to add NPC to the Recommended Uniform Screening Panel (RUSP) for all newborns.