Purpose/Aim

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive fatal motor neuron disease and the second most frequent form of spinal muscular atrophy after SMA 5q (http://www.centrodinoferrari.com/patologie/atrofia-muscolare-spinale-smard1/). The disease mainly concerns the childhood and it is characterized by a progressive muscular paralysis with intact cognitive abilities. Children do not have or soon lose the ability to walk and move voluntarily, they have a premature impairment of respiratory muscles and difficulty in nutrition. The intelligence is not compromised and in most cases the disease is precociously fatal.

SMARD1 is caused by mutations in the gene encoding the immunoglobulin protein μ2 (IGHMBP2), whose lack leads to a degeneration of the motor neurons (MNs), that are the cells responsible for the nervous signal transmission from spinal cord to skeletal muscles. To date, there is no effective therapy for this disease and there are few research programs or therapeutic strategies for SMARD1 all over the world.

Centro Dino Ferrari (University of Milan) IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico is an international reference center for patients afflicted with this disease and for their families, thanks to the opportunity of a genetic diagnosis. Moreover, and the Laboratory of Neural Stem Cells of the Dino Ferrari Center is one of the few groups carrying on a specific research program for this pathology. In particular, the goal of our research group is to develop new therapeutic strategies and specifically, to develop a gene therapy approach for SMARD1.

As a matter of fact, since SMARD1 is caused by a defect in a single gene which determines a reduction of a single protein, gene therapy approach is potentially the most effective strategy for this pathology.

This strategy consists in the transfer of the “healthy” gene into the organism in order to replace the “sick”, nonfunctional gene. The turning point in the development of gene therapy for neurological diseases has been the availability of new non-pathogenic vectors able to transfer genetic material to the central nervous system in an efficient and non-invasive way.

This therapeutic strategy allowed the development of the first gene therapy clinical study for another monogenic motor neuron disease, SMA type 1, with very promising results. Data, recently published (https://www.ncbi.nlm.nih.gov/pubmed/29091557), show that treated SMA type 1 children present a marked clinical improvement with the acquisition of the ability to sit, walk and breathe independently, when usually there is a progressive paralysis with premature exitus within the second year of life.

The project

The final aim of our project is to design and realize a clinical trial for patients affected by SMARD1 similar to the one recently concluded in SMA1 patients.

We have lately demonstrated with a paper published in Science Advances (https://www.ncbi.nlm.nih.gov/pubmed/26601156), the potential therapeutic efficacy of “healthy” IGHMBP2 gene transfer with non-pathogenic and biologically safe viral vectors (AAV9). The introduction of the “healthy” gene in the murine model affected with this pathology allows the complete rescue of the pathological phenotype, including a normal survival. These evidences represent the basis to proceed towards human clinical trials. However, the path to clinical experimentation is long and requires further pre-clinical experiments and a considerable financial support.

In particular, the goals of our project are:

1) to perform an observational and retrospective clinical study, collecting several clinical data, in order to accurately determine the disease natural history and to define the most suitable functional outcome measures. Indeed, these aspects are not yet clear and defined for SMARD1, but they are necessary to organize a clinical trial;

2) to define the treatment therapeutic window at pre-clinical level, a key and crucial aspect for clinical translation. The aim is to investigate whether gene therapy can be applied and how effective is when symptoms and signs of the disease are already present, the condition of most patients at the time of diagnosis;

3) to define the dose and the optimal route of administration;

4) to optimize the clinical grade construct in terms of cDNA and viral vector;

5) to perform further pre-clinical studies in order to validate the construct to be used in the clinic, in particular by performing toxicological and immune response studies;

6) to obtain an orphan product designation from the EMA and the approval of the experimental design of the clinical trial by the EMA.

This is certainly an ambitious project based on the data and knowledge we have achieved over the years, as shown by our publications. Each part of the project, even taking into account previous investments, is particularly onerous, and we will have to use the available funds to produce scientific works that can support the acquisition of further fundings. We are already working on Objective 1 thanks to Neurologists and Researchers currently working in our Department.

Contribute to the Smard1 Research

This project will allow us to carry out a first phase 1-2 study in SMARD1 patients. In order to carry out these studies, we need a real and concrete help to support the costs related to the experiments described in the project.

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