ARISLA DOUBLES THE FUNDS TO SUSTAIN NEW RESEARCH PROJECTS ON ALS ALSO THANKS TO THE ICE BUCKET CHALLENGE DONATIONS
THE PRESIDENT MELAZZINI: “WE WILL DEVOTE OVER 2.1 MILLION TO 15 INNOVATIVE PROJECTS THAT WON THE 2014 ARISLA CALL: WE ARE VERY SATISFIED OF ITALIAN RESEARCHERS AND READY TO LAUNCH THE ‘ICE BUCKET CALL 2015’
Milan, November, 26th, 2014 – AriSLA – Italian Foundation for ALS Research will fund all the 15 scientific research projects on ALS deemed worthy of funding by the 2014 International Scientific Committee, thanks also to the donations to the “Ice Bucket challenge” campaign, gathered by AISLA Onlus, Italian Association for Amyotrophic Lateral Sclerosis, from 31 years engaged in the care of people with ALS and in the support of research on this disease. The total investment for all new projects funded by AriSLA Foundation will be over 2.1 million euro, doubling the amount of allocated resources and the number of supported studies than last year.
PRESIDENT MELAZZINI: “WE RESPONDED TO PATIENTS’ URGENCY”
Researchers this year answered very strongly to the 6th call – says Mario Melazzini, AriSLA President – and for this reason we decided to fund all projects deemed worthy by the International Scientific Committee of the Foundation. An important result that we achieved thanks to the fundamental contribution of the donations to the “Ice Bucket Challenge” Campaign. We wanted, along with our Founders – continues Melazzini – to respond at the urgency felt by the patients’ community to accelerate as much as possible the knowledge about the disease and help developing studies of new possible treatments, by investing in research potentially transferable to the clinical practice. Now we are ready to launch the new ‘Ice Bucket 2015’ Call, thanks to the donations of thousands of Italians, to whom I renew our gratitude, for their support to our mission: fighting against ALS. “
IDENTIKIT OF THE 15 PROJECTS
The 15 funded projects have been selected from 133 Letters of Intent received, with an economic value that ranges from 45 to 300 thousand euro, and a duration between 12 and 36 months. There are two “type” of projects: “Pilot grants”, ie highly innovative project ideas that aim to test new insights in the field of basic and translational research, and “Full grants”, ie studies considered excellent for their solid scientific background and envisaged objectives.
Specifically, of the 15 projects funded, 8 are Full Grants and 7 are Pilot Grants.
The areas of funded studies refer to basic, translational, and clinical research and concern the understanding of the mechanisms of toxicity associated with mutant proteins and responsible for the onset and progression of the disease, and also the diagnosis and the search for potential therapeutic targets.
ALS is a multifactorial disease, which involves not only the motor system and motor neurons, although the latter are the main affected cells. AriSLA 2014 projects deal with the disease in its complexity, considering for example the involvement of the autonomic nervous system, which regulates the functions of the cardiovascular, digestive and urinary apparatus, whose failure has important consequences on the quality of life of ALS patients; the changes that occur in the muscles of patients, to analyze the mechanisms of onset and development of the disease; the role of the peripheral nervous system in the evolution of the disease.
About 82% of the funding provided was allocated to Full Grants, which are also geared towards clinical and translational research, closer to patients, with the aim of developing tools for early diagnosis and searching potential new therapeutic approaches.
Pilot Grants instead have the task of exploring innovative ways to understand the mechanisms of onset and development of ALS, through basic research. In particular, funded projects address the issue of epigenetics and the involvement of the immune system in ALS development.
The funding enabled 23 new research groups scattered throughout the country, in particular from Milan, Modena, Naples, Pavia, Rome, Sassari and Trieste.
The new research groups join the 74 groups and more than 154 researchers who AriSLA has supported since 2009 by investing in research activities over 6.5 million euro.
These numbers are significant for a rare disease such as ALS, for which there are still no therapies or early diagnostic markers. Even the understanding of the causes of onset, only partly due to genetic factors, is yet complex. In Italy there are about 5000 people with ALS, with a prevalence of 5-7 cases per 100,000 inhabitants and about 3 new diagnosis every day.
A PROJECTS SELECTION PROCESS THAT AWARDS THE MERIT
Funded projects have been selected after a careful “peer review” evaluation process: “peer review” is a methodology by which an International Scientific Committee of Experts evaluate the project proposals according to scientific criteria, objectivity and merit, excluding any conflict of interest. This model not only gives guarantee of impartiality in the selection of projects for funding but, in particular, it aims to promote and reward research of exellence, carried out with rigorous methods, based on innovative assumptions and focused on topics considered priorities for the knowledge and the treatment of ALS.
“Only by following an approach based on method, meritand excellence and through an efficient and transparent resources allocation – comments Melazzini – we have the real potential to defeat the disease. Our commitment is to be side by the side with researchers, to simplify, to facilitate and to make their work more efficient, always keeping an attentive eye for the person with ALS, which is for us a continuous stimulus to achieve new results, but above all he is the daily witness of hope for a future without ALS. “
– ARCI – “RNA circuitries in Amyotrophic Lateral Sclerosis pathogenesis”, coordinated by Prof. Irene Bozzoni, University of “La Sapienza”, Rome. Some genes, such as FUS and TDP-43, are responsible for the onset of ALS, and play an important role in RNA metabolism. The goal of this project is to identify the processes related to RNA expression that alter the function and survival of motor neurons, using induced Pluripotent Stem Cells (iPSCs), derived from patients’ skin, as cell model of disease – – or embryonic Stem cells (ESC) – derived from genetically modified mice,bearers of the corresponding human mutations (of FUS or TDP-43) – in order to understand how ALS evolves and develops.
– CARDI NALS – “Cardiovascular Neural Regulation In Amyotrophic Lateral Sclerosis” coordinated by Dr. Laura Dalla Vecchia, Maugeri Foundation IRCCS, Milan. In recent years it has been shown that ALS is a multisystemic disease. In fact, some evidence seems to confirm the involvement of the autonomic nervous system (ANS). The purpose of the project is to study in depth the presence and extent of any alteration in the ANS, using sophisticated methods of cardiovascular, nervous and respiratory signals analysis, as well as rating scales for a complete collection of patients’ symptoms and signs . The study will involve 80 ALS patients, whose data will be compared with those obtained in 40 healthy subjects.
– CHRONOS – “Chronic and Sporadic Mechanisms of TDP-43 Dysfunction”, coordinated by Dr. Fabian Feiguin, International Centre For Genetic Engineering And Biotechnology (ICGEB), Trieste. Although recent scientific discoveries have revealed a pathological role of the TDP-43 protein in both sporadic and familial ALS, the role and function of this protein in normal physiological conditions is still unknown. In particular, it is totally unknown its involvement in the nervous system development . The aim of the research project is to find an answer to these questions, using the Drosophila, the fruit fly, ALS model; the results will be critical to understand what are the primary events that trigger the disease and how the course and progression of ALS can be modified acting t on the TDP-43 protein expression .
– CONNECTALS – “Network degeneration in motor neuron diseases (MND): a study of the structural and functional connectomes in Amyotrophic Lateral Sclerosis and other MND”, coordinated by Prof. Massimo Filippi, IRCCS San Raffaele, Milan. Magnetic resonance imaging (MRI) is a very promising tool for the identification of early biomarkers and the reliable evaluation of ALS progression , thanks to its high sensitivity in detecting abnormalities of the brain typical of the disease and its non-invasiveness. This project will screen with MRI ALS patients, patients with Primary Amyotrophic Lateral Sclerosis, patients with progressive muscular atrophy, and healthy controls, with the aim of identifying sensitive and specific markers, in the early stages of the disease, that can differentiate patients with different motor neuron diseases also compared with healthy controls.
– GF_ALS – “Genetic engineering to produce new proteins for the protection of MN in ALS”, coordinated by Prof. Ermanno Gherardi, University of Pavia. The research project proposes to use genetic engineering techniques to produce new molecules able to protect motor neurons from the damage these cells are exposed to during ALS progression. The project is focused on the study and manipulation of a growth factor involved in embryonic development of different groups of neurons. The new proteins that will be developed are going to be better than the natural counterpart and produced in sufficient quantities for future clinical use.
– GRANULOPATHY – “VCP and autophagolysosomal pathway: guardians of proteostasis and stress granule dynamics. Unraveling their applications in ALS”, coordinated by Dr. Serena Carra, University of Modena and Reggio Emilia. One of the features of ALS is the formation within the cells of stress granules (SG), made of altered protein aggregates . The SG are dynamic structures that are formed following a cellular stress, with protective function The purpose of the project is to study the mechanisms that lead to the accumulation of protein aggregates and SG, concurring to cause toxicity and cell death. The hypothesis is that the processes that regulate protein quality control and SG are intimately connected and, therefore, using different patient-specific cell models (fibroblasts, lymphoblasts, induced pluripotent stem cells – iPSCs) bearing mutations in different genes, the study will seek to modulate some components of these processes, in order to identify new mechanisms involved in ALS.
– PATH-FOR-ALS – “P2X7 as target for ALS”, coordinated by Dr. Cinzia Volontè, National Research Council (CNR), Rome. Neurodegenerative diseases characterized by the involvement of the inflammatory system, such as ALS, showed a compromised communication between neurons and microglia. In particular, the P2X7 receptor, located on microglia cells, appears to play a very important role in this communication. Previous experimental results obtained by the research team have demonstrated the ability of an inhibitor of the P2X7 receptor to reduce neuroinflammation and improve pathological features of ALS in an animal model of the disease. The research project aims to carry out a comparative analysis in the same animal model to test the effectiveness of two new inhibitors of the P2X7 receptor.
– smallRNALS – “The role of dysregulation of small RNAs and proteomic analysis of patient-derived induced pluripotent stem cells”, coordinated by Dr. Stefania Corti, University of Milan. Alterations in the expression of microRNAs (miRNAs), small RNA molecules that do not directly translate into proteins, but are active in gene expression regulation , have recently been involved the onset of ALS. The project aims to study their role in the development of the disease, using a very promising cell model: induced pluripotent stem cells (iPSCs). The iPSCs allow to recreate in the laboratory patient-specific characteristics and heterogeneity of the disease. The objective of this project is to identify patient-specific differences in miRNAs expression and verifying if the modulation of these small RNAs may have a neuroprotective effect on motor neurons differentiated from iPSCs of ALS patients.
–ALSHDCA1 – “HDAC-1 TDP-43 interaction: implication for ALS”, coordinated by Prof.Claudia Crosio, University of Sassari. The goal of the project is to extend the knowledge about the role of TDP-43 protein in the onset and progression of ALS, in particular in relation to its interaction with some epigenetic factors that induce modification in protein expression. Through the use of cellular and animal models the project will verify the involvement of the interactions between normal or mutant TDP-43 with some epigenetic factors – such as histone deacetylases – in determining the onset and progression of ALS.
–DC-ALS – “Activation state and Functionality of Dendritic cells from pheripheral blood of ALS patients”, coordinated by Prof. Francesca Granucci, University of Milano-Bicocca. Dendritic cells (DC) are key cells of the innate immune system that can induce other cells, such as macrophages and microglia, to assume pro-inflammatory or anti-inflammatory characteristics, respectively promoting or slowing disease progression. They also play a key role in the removal of toxic aggregates. Recent studies have shown a clear role of systemic chronic inflammation in influencing the neurodegeneration in ALS and they also have demonstrated the presence of functionally impaired dendritic cells in patients peripheral blood. These cells are more inclined to promote the activation of pro-inflammatory cells. The project aims to understand the role of dendritic cells in ALS patients blood, in relation to the disease stage , and to study how and when these cells are activated and begin to produce pro-inflammatory signals.
-CONSLA – “Setting of a new preconditioning model for ALS”, coordinated by Dr.Giuseppe Pignataro, University of Naples. Preconditioning (PC) is the phenomenon by which an organ, following exposure to harmful subliminal stimuli, is able to adapt itself in order to be protected from subsequent attacks of greater magnitude. Some preliminary results have suggested the possibility of obtaining a degree of protection in ALS animal models, using as preconditioning stimulus low doses of BMAA, an amino acid obtained from the seeds of cycads, whose use has been linked to the onset of ALS among inhabitants of the island of Guam in the Pacific, who used to eat the flour produced from seeds containing this amino acid. The goal of the research project is to characterize the first model of preconditioning in ALS, in order to identify potential new targets.
-EpiALS – “Study of the role of epigenetic regulators in the pathogenesis of ALS”, coordinated by Dr. Camilla Bernardini, University Cattolica of Sacro Cuore, Rome. The majority of studies aimed at understanding the ALS etiology have focused on the analysis of motor neuron, without considering the changes that occur in the muscle. The project intends to study the mechanisms of degeneration in the muscles, starting from the analysis, in ALS patients, of epigenetic factors, called histone deacetylase (HDAC), and their inhibitors, which have been recently proposed for the treatment of certain neurodegenerative diseases. The inhibition of histone deacetylase will be performed, as well as through existing HDAC inhibitors, also using some molecules that mimic the action of microRNAs, small molecules of endogenous RNA involved in the regulation of gene expression, able to silence specifically target genes.
-EX ALTA – “EXploring the peripheral nervous system path to unravel Amyotrophic LaTerAl sclerosis”, coordinated by Dr. Angelo Quattrini, ISSCR San Raffaele, Milan. The degeneration of peripheral nerve fibers is one of the earliest events in ALS patient and a major cause of muscle weakness. Recently, the research group has developed and validated the withdrawal of the obturator nerve, innervating part of the thigh muscles, in order to support reliable diagnosis from the very earliest stages of the disease. The aim of this study is to identify the mechanisms that act in the peripheral nervous system that result in the progression of the disease and in the loss of nerve fibers in ALS. In order to identify the differences between ALS patients and patients with other neuropathies in this project will be analyzed human tissues.
-FUSMALS – “Functional Interaction of FUS with SMN as A Common Pathogenic Pathway For Motor Neuron Diseases”, coordinated by Dr. Mauro Cozzolino, National Research Council (CNR), Rome. SMN is a protein critical for the regulation of some key aspects of RNA metabolism that regulates gene expression , allowing the translation of the information from the DNA into proteins. SMN is also implicated in Spinal Muscular Atrophy (SMA), a disease that affects selectively motor neurons, like ALS. The research group has previously shown that SMN interacts with the FUS protein, which is involved in the onset of some familial forms of ALS. The hypothesis is that these two proteins cooperate in regulating RNA metabolism and, therefore, damages or a mutations of one of the two proteins may cause motor neuron degeneration.
-MAMMALS – “MiRNAs as microglia modifiers for ALS”, coordinated by Dr. Chiara Parisi, National Research Council, Rome. The microglial cells are cells of the immune system that offer the first and main active immune defense in the central nervous system. The presence of a damaged motor neurons in ALS, makes them constantly active. Recently it was shown that the production of toxic molecules by microglial cells depends on alteration of family members of NF-kB, a transcription factor that causes the release of toxic molecules through the control of proteins expression. In order to stop this process, the research group proposes the use of a particular microRNA, which is able to regulate the members of NF-kB family , in order to modulate the production of toxic or neuroprotective molecules.