0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

AISLA.1 – Validation of a combined pharmacological treatment to slow progression of disease…
to reduce muscle atrophy following sciatic nerve transection in rats [Fernandez
et al. 1995]. More recently we obtained preliminary results in SOD1-
mutant mice demonstrating a significant prolongation of their life span after
LAC treatment (+ 8%) which was magnified by the co-treatment with riluzole
(+26%).
Objectives of this study will be to evaluate progression of disease and life
span in transgenic mice, and to monitor molecular and cellular parameters
during the treatment.
The rationale is based on the knowledge that:
1. a multidrug intervention is the only way to intercept simultaneously,
and thus effectively, the various pathways concurring to the pathogenesis of
ALS;
2. those pathways are most probably activated years before onset of symtoms,
thus making prevention of damage unfeasible in ALS patients; however,
any therapy effective in rescuing surviving motoneurons should result in preserving
motor function and therefore in longer life expectancy and better
quality of life for patients;
3. multidrug clinical trials are difficult to carry out in patients and they
usually receive only support treatment (including drugs that provide very
modest benefit, i.e. riluzole) whereas novel therapeutic protocols are very
urgently needed;
the use of a combination of drugs already approved for human use may overcome,
at least in part, the difficulties usually encountered when trying to
translate protocols from mice to man.
DESCRIPTION OF THE PROJECT
This study is based on the collaboration of three units with complementary
expertise.
– U.O. 1 (Maria Teresa Carrì, Laboratorio di Neurochimica, Fondazione
Santa Lucia, e Dipartimento di Biologia, Università di Roma Tor Vergata ) has
extensive and documented experience in the biomolecular mechanisms
responsible for SOD1 toxicity in vitro.
– U.O. 2 (Caterina Bendotti, Dipartimento di Neuroscienze, Istituto di
Ricerche Farmacologiche Mario Negri, Milano) has long and documented experience
on the study of animal models of ALS, and in particular of the clinical
and histomolecular profile of SOD1G93A transegnic mice.
– U.O. 3 (Marina Bentivoglio, Dipartimento di Scienze Morfologico-Biomediche,
Università di Verona) has long and documented experience on the
neuropathological analyses in animal models of neuroinflammation and neurodegeneration,
including specific expertise in SOD1G93A transgenic mice.
The experimental plan will be perfomed as follows:
U.O. 2 will have the task to perform the treatments and assess the motor
behavior and the survival of mice until sacrifice. The same unit will sample
tissues at proper times for biochemical and histopathological investigations.
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