Targeting the endocannabinoid system to treat epilepsy in Niemann Pick disease type C

Awardee: Lola Ledesma

Institution: Centro Biologia Molecular Severo Ochoa

Grant Amount: $40,140.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Pharmacoresistent epilepsy is frequently found in NPC patients. This condition impact heavily in the quality of life of the patients and their families. Several studies have reported the ability of cannabinoids to reduce the frequency of seizures with a safe profile even in pediatric population. We have also shown the downregulation of the endocannabinoid system in the brain of an NPC mouse model and patient. We thus propose the enhancement of the endocannabinoid system as anti-epileptic treatment in the disease. We will assess the efficacy and safety of this strategy in a mouse model for NPC using oral administration of exogenous cannabinoids or of an inhibitor of the endocannabinoid degrading enzyme FAAH.

Leveraging proteostasis to improve Niemann-Pick C gene therapy

Awardee: Mark Schultz

Institution: Regents of the University of Michigan

Grant Amount: $50,010

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Niemann-Pick C is a genetically inherited disease caused by an abnormal accumulation of cholesterol. This cholesterol build-up commonly occurs due to a defect in a gene called NPC1. In Niemann-Pick C mouse models, adding back a fully functional NPC1 gene via gene therapy improves but does not fully correct the disease. Here we will leverage the information we have gained on protein folding to significantly increase the efficacy of Niemann-Pick C gene therapy.

Deciphering variants of unknown significance in Niemann Pick Type C

Awardee: Evgueni Ivakine

Institution: Hospital for Sick Children

Award Amount: $47,630

Funding Period: February 1, 2021 - January 31, 2022

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Summary:

As we enter an age where we understand more about genetic disease, we are beginning to regularly implement genome sequencing and personalized medicine in clinical practice. These efforts are hampered by a lack of knowledge about how mutations contribute to disease. This is particularly the case for diseases like Niemann-Pick disease type C (NPC), a rare genetic disease in which most patients present with a mutation that has not previously been reported. This leads to lengthy wait times between presentation and definitive diagnosis, as specialized laboratories are required to biochemically diagnose each potential patient. Through our work, we aim demonstrate a new method to quickly and easily create every possible mutation in each DNA base in a critical region of the the NPC1 gene using next-generation CRISPR-based gene editing technologies. Once we have generated a group of these mutant cells, we will perform a functional test to rapidly ascertain if each would likely lead to developing the disease or not. After identifying disease-causing mutations, we will apply a drug, currently undergoing clinical trials for NPC, to further classify the disease-causing mutations as responders or non-responders to this treatment.

Testing Niemann-Pick C proteostasis therapeutics on human iPSC derived neurons

Awardee: Mark Schultz

Institution: Regents of the University of Michigan

Awarded Amount: $61,637

Repurposing FDA-approved drugs for Niemann Pick C Disease

Awardee: Yamuna Krishnan

Institution: University of Chicago

Award Amount: $62,340

AAVrh.10-mediated Npc2 Gene transfer for the treatment of Npc2 Deficient Niemann-Pick disease

Awardee: Dolan Sondhi

Institution: Weill Cornell Medicine

Award Amount: $49,645

Funding Period: January 1, 2018 - December 31, 2018

Targeting molecular chaperone HSP90 to treat NPC1 disease

Awardee: Nina Pipalia

Institution: Weill Cornell Medical College

Award Amount: $49,645

Funding Period: January 1, 2018 - December 31, 2018

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Publications:

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

Carboxyl lysosphingomyelin as a Biomarker for Diagnosis and Assessment of Treatment of NPC Disease

Awardee: Xuntian Jiang

Institution: Washington University School of Medicine

Award Amount: $51,000

Funding Period: January 1, 2017 - December 31, 2017

Impact on Niemann-Pick C disease of the cross-talk between the c-Abl and the TFEB signaling pathways

Awardee: Silvana Zanlugo

Institution: Pontificia Universidad Católica de Chile

Award Amount: $51,000

Funding Period: January 1, 2017 - December 31, 2017

Characterization of NPC1-I1061T proteostasis machinery for development of NPC therapeutics

Awardee: Andrew Lieberman

Institution: University of Michigan

Award Amount: $53,000

Funding Period: January 1, 2016 - December 31, 2016

Targeted AAV gene therapy for vertical supranuclear gaze palsy and dysphagia

Awardee: Charles Vite

Institution: University of Pennsylvania

Award Amount: $53,500

Funding Period: January 1, 2016 - December 31, 2016

CNS gene therapy to restore NPC1 protein expression in cerebellar Purkinje cells and delay or prevent disease onset in feline Niemann-Pick type C1 (NPC1) disease.

Awardee: Brittney Gurda

Institution: University of Pennsylvania, School of Veterinary Medicine

Award Amount: $35,000

Funding Period: January 1, 2015 - December 31, 2015

Dual targeting of defective lipid and metal pathways in Niemann-Pick type C disease: an in vitro pilot study

Awardee: Ashley Bush

Institution: The Florey Institute of Neuroscience and Mental Health

Award Amount: $50,000

Funding Period: January 1, 2015 - December 31, 2015