Gene therapy of animal models of lysosomal storage diseases

OBJECTIVES
This workpackage will focus on state-of-the-art gene transfer technologies for treatment of systemic signs in animal models of Gaucher and Pompe diseases as well as of Mucopolysaccharidosis VI (MPS VI) and Multiple Sulfatase Deficiency (MSD).

We selected these disease targets because:

1. They are common LSDs (Gaucher and Pompe).
2. Involvement of non-CNS sites is the sole or most important feature of the disease (Gaucher, MPS VI and Pompe).
3. The disease models are extremely severe and therefore the therapeutic success is both highly desirable and paradigmatic for other types of LSDs (MSD).

As gene transfer strategies we propose to pursue:

1. Ex vivo modification of autologous hematopoietic stem cells (HSC) for type I Gaucher.
2. In vivo gene transfer to tissues like liver and muscle using adeno-associated viral (AAV) vectors for Pompe, MPS VI and MSD.

PARTICIPANT NUMBER

2 – FTELE.IGM (Andrea Ballabio)
1 – DPFII (Generoso Andria)
5 – ULUND (Stefan Karlsson)

LIST OF DELIVERABLES
31. Development of safe retroviral vectors completed. (12 months).

32. Development of AAV vectors completed. (12 months).

33. Retroviral vector safety and insertion site analysis completed. (36 months).

34. Evaluation of efficacy of AAV vectors in animal models completed. (36 months).

LIST OF MILESTONES
M5.1 Determination of the GD HSC engraftment percentage. (Month 18).

M5.2 Production and characterization of high titer AAV vector preps to be tested in animal models of MPS VI, PD, MSD. (Month 18).

M5.3 Successful gene therapy in mice with type 1 Gaucher disease using safe vectors and low risk myeloablation. (Month 36).

M5.4 Correction of MPS VI, PD and MSD phenotype following AAV-mediated gene transfer. (Month 36).