Gene Therapy for Neurometabolic Disorders

 

The research activity of our group is focused on the development of gene therapy strategies for diseases affecting the nervous system, both central (lysosomal storage diseases) and peripheral (pain, genetic and acquired neuropathies) and on the elucidation of the molecular mechanisms implicated in the development of these pathologies combining the use of animal models, tissue cell culture and viral vectors.
Funding: ISCIII; Feder-EU; AGAUR, Marató TV3

MAIN RESEARCH LINES:
 

1) Study of the tropism of different gene therapy viral vectors in the peripheral nervous system
Gene transfer to the peripheral nervous system (PNS) is particularly challenging as it involves several cell types, most of them post-mitotic. Efficient gene transfer to certain cell types of the PNS can be of great interest for gene therapy for neurological diseases or for pain treatment. Also important, delivery or inhibition of target molecules with viral vectors can be used as a tool to analyze physiological processes in the PNS, such as interactions between glia and neurons, retrograde or anterograde transport, nerve regeneration, etc. Within the aim to determine the most efficient gene transfer vectors for each cell type in the PNS, we are characterizing the tropism of different pseudotypes of AAV vectors and different human and non-human adenoviral vectors through different routes of administration.
 
2) Gene therapy for diabetic neurological complications
Diabetic complications involve both sensorimotor and autonomic components of the peripheral nervous system (PNS). Sensorimotor neuropathy developed by diabetic patients is the most common peripheral neuropathy affecting in different degrees all types of nerve fibers and causing loss of pain sensation, burst sensation and cutaneous hyperestesia, typically starting at the feet and the lower part of the legs but progressing to hands and arms. In more advanced stages, foot ulcers and neuropathic deformities appear, which could lead to 40% of the non-traumatic limb amputations.
The pathology of diabetic sensorimotor neuropathy is characterized by axonal atrophy and demyelination, leading to nerve fiber loss followed by abnormal regeneration of these fibers. Despite insulin treatment or pancreas transplantation, progression of diabetic neuropathy is not stopped, indicating the need for a specific treatment at early stages of the diabetes.
Our team is studying the molecular mechanisms leading to the development of diabetic neuropathy, using primary cell cultures and mouse models of the disease, with the aim to elucidate new therapeutic targets for this complication of the diabetes. In more detail, we are studying the effect of hyperglicemia in the demyelination of the PNS and the role of trophic factors or other molecules implicated in the cellular signaling between sensory neurons and Schwann cells to stimulate the expression of myelin proteins and the regeneration of the PNS.
 
3) Understanding and treating Mucopolysaccharidosis type VII
Gene therapy is one of the most attractive treatments for diseases affecting the central nervous system (CNS) since blood-brain-barrier impairs delivery of systemically administered drugs to the cerebral parenchyma. Currently, some gene therapy clinical trials are ongoing for the treatment of some lysosomal storage diseases (LSD) with neuronal involvement, which are progressive neurological diseases affecting young children. However, the proper development and evaluation of these therapies requires understanding how cell signaling pathways are affected in these diseases and what is the impact on the viability or function of LSD cells and particulary in neurons. Other organs like bone or heart can be difficult to correct, even with high serum enzyme levels. We are paying particular attention to these tissues in a mouse model of Mucopolysaccahridosis type VII.