Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Understanding and treating neurodegeneration caused by mucopolysaccharidoses

Project Coordinator

Universitat Autònoma de Bracelona Biochemistry and Molecular Biology CBATEG, Campus UAB


Eric Kremer Istitut de Génétique Moleculaire de Montpellier UMR5535 Montpellier, France
Jean-Michel Verdier Ecole Pratique des Hautes Etudes Biology & Health Montpellier, France
Johannes Schwarz Universität Leipzig Klinik für Neurologie Leipzig, Germany

Publications of the CAV-4-MPS project

Major results of the project

Lysosomal storage diseases (LSD) are a group of autosomal recessive metabolic disorders leading to multi-systemic damage and death. LSD form collection of ~60 orphan diseases, primarily affecting children. Most of these disorders result from deficiencies in enzymes normally implicated in the catabolism of macromolecules inside lysosomes Almost 60% of the lysosomal storage disorders lead to untreatable neurodegeneration. Among LSD, mucopolysaccharidoses (MPS) have an overall incidence of 1 in ~29,000 live births. Similar to other MPS, mucopolysaccharidoses type VII (MPS VII) patients often present with the mental retardation, variable aggression, hyperactivity and/or tempers. No option is available for the treatment of the neuronal deficits in MPS patients but as suggested by clinical results in Canavan and Parkinson’s disease, gene transfer offers substantial potential. However, this strategy of therapeutic intervention also brings unique obstacles - in particular the need to address feasibility, efficacy and safety. The foundation of this project was to assess the potential of a new platform, canine adenovirus type 2 (CAV-2) vectors, which transduce neurons very efficiently, for treating the neurological symptoms of MPS VII, as a model of lysosomal storage disease. This is a genetic rare disease that needs low but sustained expression of the missing enzyme for the whole life of the patient. Our objective was to bring a novel viral vector "from bench to bedside" for MPS VII by this particular vector to demonstrate efficacy and safety in the diseased brain of MPS VII mouse and dog models and in healthy primates. The challenge was the distribution throughout the brain because mucopolysaccharidoses, and in particular MPS VII, are disorders affecting the entire brain.

We obtained consistent and extremely encouraging results in, both in MPS VII mouse and dog model. Following intracranial administration of helper dependent CAV2 vector coding for the missing enzyme in MPSVII, we were able to show short and long-term expression of the therapeutic enzyme in both models, leading to clearance of lysosomal storage accumulation at the injection point but also in many distal areas and correlating with the decrease in secondary-elevated lysosomal enzymes and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, behavioural tests in treated mice show significant improved learning and long-term memory, similar to healthy mice. So, we demonstrate the potential of these vectors in achieving global brain correction in MPS VII mice and dogs. Moreover, in non-human primates, the vector preferentially transduce neurons from both hemispheres as in mice and dogs, and leads to safe and long-term stable expression.

E-Rare 2012 - Created by Toussaint Biger