Niemann-Pick C1 (NPC1) disease is a lipid-storage disorder, characterized by cerebellar ataxia, unbalanced standing and neurological manifestations including dementia. Several NPC1 disease-causing mutations have been identified in Npc1 gene, encoding a protein residing in late endosomes/lysosomes that mediates the efflux of endocytosed cholesterol.
The massive loss of cerebellar Purkinje cells is the prominent feature of NPCD, resulting in progressive motor impairment. Studying the cerebellar development , we observed a defective proliferation of granule neurons that affects the size of all cerebellar lobules of Npc1-deficient mice. Moreover, defects in exocytosis/mobilization of synaptic vesicles (rich in cholesterol) as well as an imbalance between inhibitory/excitatory neurotransmission were observed in Npc1-deficient mice (Xu et al., 2010).
No effective cure is available for NPC1 disease; 2-hydroxypropyl-ß-cyclodextrin promoting the cholesterol movement from endosomes to cytosol, represents the major treatment, but has a limited penetration of blood-brain barrier, presents dose-dependent cytotoxicity and has a short half-life in bloodstream.
Since the damaging of intracellular cholesterol trafficking causes neuronal dyshomeostasis, this project is designed to identify alternative or supplementary drugs counteracting neuronal/glial dysfunction. Although these drugs would not rescue the defective intracellular trafficking of cholesterol, they are expected to ameliorate the clinical/cellular phenotypes, thus delaying the onset of motor and neurological deficits.
To this end, using Npc1 nmf164 mouse model that mimics the most frequent form of NPCD, I will investigate whether and how the administration of ceftriaxone and taurine, an antibiotic and amino-acid respectively:
- produce synergetic neuroprotective and antioxidant effects;
- improve cerebellar motor abilities;
- restore physiological processes of cerebellar functioning that are deeply affected in NPCD.
Niemann-Pick C1 (NPC1) is an inherited disorder, ultimately fatal, presenting with variable neurovisceral symptoms. Estimated incidence is of 1:92,104, or 1.12 affected patients per 100,000 live births, but this value is likely underestimated because of misdiagnosis. In the case of NPC1 disease, children are born with normal abilities and only develop disease in infancy or later in the first decade (the juvenile form modeled by our Npc1 nmf164/nmf164 mice).
This delay in symptoms presents an opportunity to treat the disease before manifestations appear, thanks also to newer genomic techniques that provide newborn screening for hundreds of diseases.
The design of this proposal overcomes major intrinsic limitations of presently available ß¿cyclodextrin based therapies, as intrathecally administration. In this regard, it is worth noting that taurine is a common component of nutritional supplements and energy drinks, with an excellent safety profile in human clinical trials (Shao and Hathcock 2008) and the properties of ceftriaxone allow the subcutaneous instead of intrathecal administration, which can surely improve patient compliance and ease of administration, drastically.
Despite these drugs would not rescue the defective intracellular trafficking of cholesterol, they are expected to ameliorate the clinical/cellular phenotypes, thus delaying the onset of motor and neurological deficits, with the objective of improving the patient's overall quality of life.