Disease Characteristics: NPC is a rare, inherited and fatal neurodegenerative disease. 95% of NPC cases are caused by mutations in the NPC1 gene that encodes for NPC1, a large protein which is embedded in the lysosomal membrane. When it is mutated or absent, both cholesterol and sphingolipids accumulate in the brain, liver, lungs, bone marrow, and spleen. Sphingolipids are known to play important roles in signal transduction and nerve-fibre insulation, and their abnormal storage leads to irreversible neurological damage. There are several disease subtypes which are categorised by the age of onset of neurological disease. The patients develop progressive disabilities such as impairment in swallowing and speech, epilepsy, cerebellar ataxia (an inability to coordinate balance, gait, extremity and eye movements), and progressive dementia. The speed of progression of symptoms depends on the age of onset, which ranges from just after birth through to late adulthood.
Unmet Need: There are no approved treatments for NPC in the US. Miglustat is approved in the EU, but its use only slows disease progression. There are no curative treatments currently approved for NPC and there is a significant need to improve the standard of care.
Epidemiology: The incidence of NPC is estimated to be approximately 1:100,000 live births worldwide.
Intracerebroventricular (ICV) administration of BGT-NPC in neonatal and juvenile NPC mice showed enhanced NPC1 protein expression, resulting in a significant improvement of animal survival, attenuated neuropathology, as well as improved locomotor deficit. Following a successful Scientific Advice meeting with the MHRA and a Type B Pre-Investigational New Drug Application (IND) Written Response from the FDA, subject to initiating a vector manufacturing campaign, we plan to initiate safety and biodistribution studies in rodents in 2024 ahead of initiating a single, Phase 1/2/3 clinical trial.
BGT-NPC has received Orphan Drug Designation by the European Commission (EC) and the U.S. Food and Drug Administration (FDA) as well as Rare Pediatric Disease Designation (RPDD) by the FDA for the treatment of NPC.
Hughes MP, Nelvagal HR, Coombe-Tennant O, Smith D, Smith C, Massaro G, Poupon-Bejuit L, Platt FM, Rahim AA. A Novel Small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann–Pick Type C1 Disease. Cells. 2023; 12(12):1619. https://doi.org/10.3390/cells12121619
Hughes MP, Smith DA, Morris L, et al. AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease. Hum Mol Genet. 2018; 27(17):3079-3098. doi:10.1093/hmg/ddy212 (NB: BGT-NPC includes a novel promoter not described in this paper)
International Niemann–Pick Disease Alliance (INPDA) https://www.inpda.org/
National Niemann Pick Diseases Foundation (NNPDF) https://nnpdf.org/
Niemann-Pick UK (NPUK) https://www.npuk.org/
