Splice switching methods for the treatment of Pompe disease – POMPE

Pompe disease (GSD-II) is an inherited recessive metabolic myopathy (incidence: 1/40,000) caused by mutations in the GAA gene encoding the acid alpha-glucosidase enzyme. We here developed an entirely new concept for treating the majority of patients with Pompe disease based on a RNA splice modification of the mutated GAA transcripts, and this novel strategy could bear the potential to cure this devastating disease. In particular, we propose a pharmacological approach to allow normal inclusion of exon-2 into the GAA-mRNA in patients with the c.-32-13T>G common mutation by using antisense oligonucleotide (AON) based tricycle-DNA (tcDNA) chemistry, thereby overcoming the deleterious effect of a mutation involved in Pompe disease in the majority of late-onset patients.

Our main bench-side aims are:
1. Identify tcDNA sequences which most efficiently restore GAA enzyme activity in patient cells
2. Determine pharmacokinetics of tcDNA following systemic administration in mice
3. Determine potential immune response
4. Determine toxicity profile of tcDNA
5. Identify tcDNA-AON binding proteins

Our main bed-side aims are:
1. Establish a detailed Pompe patient data base
2. Perform a natural History Study
3. Perform a biomarker study
4. Complete molecular studies

Our bed- to bench-side aim is:
1. Develop a Pompe xenograft model to proof tcDNA therapy efficiency on differentiated human skeletal muscle.

The herein proposed research will advance this novel therapeutic strategy and the Pompe patient cohort to clinical trial readiness. To achieve this aim we will assemble the U1179 research laboratory, which is specialized in the development of biotherapies for neuromuscular disorders, and expert clinicians for Pompe disease with access to most patients of the Ile-de-France cohort. We are confident that herein developed tcDNA will provide a suitable treatment option for patients with late-onset Pompe disease for whom current treatments are ineffective and overpriced.