The research undertaken in this laboratory is focused mainly on the study of Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder that affect the neuromuscular system causing progressive muscle wasting and paralysis until death usually within 2-5 years of diagnosis. In particular, our work is aimed at understanding the mechanisms involved in motor neuron degeneration and neuromuscular dysfunction of transgenic mice carrying a mutated form of superoxide dismutase 1 (SOD1) that recapitulate many features of the human pathology. The two main objectives of our research program are:
- to identify pathological mechanisms that can be targeted with potential therapeutic agents and approaches
- to find novel biomarkers that can help to predict the onset and the progression of the disease
The overall aim is to develop effective therapeutic strategies able to hamper the course of this debilitating and fatal neurodegenerative disease and to provide signatures helping in the stratification of patients for the clinical trials.
ALS: study of the mechanisms governing the course of disease
ALS is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. We found that two ALS mouse models carrying the same SOD1G93A mutation showed marked difference in the onset and progression of disease due to their different genetic background. This project aims to investigate the mechanisms underlying the difference in the disease for providing new prognostic stratification and new disease-modifying therapeutic options to be translated to patients. In particular we undertook a comparative analysis of the two mouse models using a broad spectrum of analytical techniques including molecular biology, immunohistochemistry, confocal microscopy, MRI, transcriptomic, proteomic and metabolomic analysis. This approach has enabled us to make significant discoveries that have revealed mechanisms as potential disease modifiers (i.e. immunomodulation) and identify novel targets for biomarkers and therapeutic strategies.
ALS: role of neuroinflammation and immune response
Among the mechanisms responsible for the different disease progression in ALS mouse models, we have demonstrated an important role of the immune response, especially at the level of the peripheral compartment of the neuromuscular system. For example, we have shown that an increase of MHCI and CCL2 in the nerve as well as the recruitment of macrophages and lymphocytes at the nerve and neuromuscular junction, is essential for delaying the onset and progression of symptoms. On the contrary, in the spinal cord a prolonged neuroinflammation is detrimental for the motor neurons. This opposed role of the inflammation could explain why anti-inflammatory and immunosuppressive drugs did not show efficacy in ALS patients. We are now investigating new strategies that may potentially interfere with the immune response in the different compartment by using the viral vector technology to modulate in a cell-specific manner different immune molecules.
Genetic SLA: development of a new platform of ALS mouse models for preclinical trials
We have a long-standing expertise in undertaking preclinical trials of potential therapeutic agents in SOD1G93A mouse models of ALS. However, although studies carried out on mice with SOD1 mutations gave very important information on the development and evolution of the disease, they have not yet led to the development of effective therapies for patients. This is partially due to the fact that only 3% of patients carry SOD1 gene mutation. To date the C9orf72 gene mutation is the one most represented in familial and sporadic ALS patients while the accumulation of TDP43 aggregates in the central nervous system is the typical hallmark of all patients with ALS. Thus, we decided to implement our animal facility with two other murine models of the disease, the C9orf72 mutated mice and the transgenic mice overexpressing wild type human TDP43. We are now deeply study these mice by using a broad spectrum of analytical technique such as behavioral testing, in vivo muscle electrophysiology recording, immunohistochemistry, biochemistry and molecular biology. A combination of these mouse models allow to undertake and validate preclinical trials of potential therapeutic agents.
International Consensus on Cardiopulmonary Resuscitation.