CYP46A1 AS A NEW THERAPEUTIC TARGET IN NIEMANN-PICK TYPE C DISEASE

Investigador: Elsa Rodrigues
Instituição: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de
Lisboa (FF/ULisboa), Lisbon, Portugal

Due to its importance in neuronal function, we have been devoted to the characterization of the molecular pathways involved in the control of brain cholesterol metabolism, focusing on the role of CYP46A1. The neuronal specific cholesterol 24-hydroxylase, encoded by the cytochrome P450 CYP46A1 gene, is responsible for the conversion of cholesterol into 24S-hydroxycholesterol, which accounts for the major elimination pathway of brain cholesterol. Due to its importance in cholesterol elimination we hypothesized that CYP46A1 could be a new therapeutic target in Niemann-Pick type C disease (NPC1 - Rare Disease ORPHA646). NPC disease is a lysosomal
storage disorder, characterized by cholesterol accumulation in the late endosomes/ lysosomes compartment, which results from mutations in NPC1 or NPC2 genes. The most dominant feature is the progressive neurodegeneration leading to premature childhood death.

Abstract

Due to its importance in neuronal function, we have been devoted to the characterization of the molecular pathways involved in the control of brain cholesterol metabolism, focusing on the role of CYP46A1. The neuronal specific cholesterol 24-hydroxylase, encoded by the cytochrome P450 CYP46A1 gene, is responsible for the conversion of cholesterol into 24S-hydroxycholesterol, which accounts for the major elimination pathway of brain cholesterol. Due to its importance in cholesterol elimination we hypothesized that CYP46A1 could be a new therapeutic target in Niemann-Pick type C disease (NPC1 - Rare Disease ORPHA646). NPC disease is a lysosomal
storage disorder, characterized by cholesterol accumulation in the late endosomes/ lysosomes compartment, which results from mutations in NPC1 or NPC2 genes. The most dominant feature is the progressive neurodegeneration leading to premature childhood death.
We propose a work plan based on preliminary results and on a methodological multidisciplinary strategy which will allow to understand if modulation of CYP46A1 activity/ expression might be a novel strategy for NPC treatment, uncover the underlying mechanisms involved, and open a new therapeutic avenue for this disease. Therefore, we will: i) Determine if CYP46A1 overexpression in vivo can decrease neurotoxicity in NPC1 mice brain and improve mouse phenotype by delivering AAV-CYP46A1 to the cerebellum of Npc1tm(I1061T) mice; ii) Characterize the cytoprotective mechanisms activated upon CYP46A1 up-regulation that prevent from cholesterol accumulation induced neurotoxicity, focusing on mitochondria function and dynamics.
The PI has brought together a highly motivated team, from two national centers of excellence (iMED.ULisboa and IMM), with a solid scientific background and expertise in all the techniques necessary to carry out the proposed studies. This project also benefits from an ongoing international collaboration, with Dr. Nathalie Cartier and her team (INSERM, France), especially for AVV vectors and stereotaxic injections.

Consulte Grelha de Avaliação