The overall goal of the project is to study specific lysosomal diseases, to understand the pathophysiology, to determine the natural history of these rare diseases in order to develop tools to measure therapy efficacy and to test and develop novel therapeutic approaches utilizing appropriate animal models of human disorders.

The specific objectives are as follows:

1. Characterize the pathophysiology of MSD, MPSVI and PD to identify disease mechanisms and markers. This characterization will be done utilizing specific markers and assays that will allow quantifying and verifying the mechanisms studied.

2. Determine factors that modify clinical diversity between PD patients bearing the same GAA haplotype. This will be determined by using specific assays.

3. Identify tissue-pathology markers as determinants of PD stage. The success of therapeutic intervention seems largely determined by the stage of disease at start of treatment. Furthermore, these markers could help in predicting efficacy of therapy.

4. Characterize the natural history of a subset of LSDs in order to have the correct tools to evaluate treatment efficacy and to obtain information to develop standardized European protocols for the different LSDs, starting with Pompe disease and the MPSVI. This will allow collecting homogeneous information on a large number of patients and, ultimately, will be useful to further validate the information available until now on the therapeutic outcome.

5. Explore the use of enzyme enhancement by pharmacological chaperones, for the treatment of Pompe disease.

6. Determine the effect of miglustat and other substrate inhibitory analogues, such as the morpholino compounds, on de novo biosynthesis of glucosylceramide and determine whether their action serves as an inhibitor of cytokine release that accompanies Gaucher disease.

7. Develop novel gene therapy approaches using state-of-the-art gene transfer technologies based on AAV vectors for therapy of systemic signs of lysosomal storage diseases (LSD).