Experimental Treatments for Pompe Disease

There are a number of experimental treatments for Pompe disease in various stages of development. These treatments are not yet approved, but they offer hope of more options and better outcomes for Pompe patients in the future.

Gene therapy

Researchers at Duke Health are developing a gene therapy approach for Pompe disease. This treatment uses a virus to deliver a healthy copy of the gene that is mutated in Pompe, the GAA gene, into the patients’ liver cells. Viruses are routinely used in gene therapy to deliver genetic material because they are specialized to do this to replicate. Viruses used in gene therapy have been altered so they are able to introduce genetic material into a cell, but can no longer replicate themselves.

research group at the University of Florida is working on a gene therapy approach that delivers the healthy gene to the patients’ entire system via an injection into the bloodstream. This approach may allow the therapy to be effective in a variety of tissues, including neurons that also are affected by Pompe disease. They currently are recruiting patients for a Phase 1 clinical trial (NCT02240407) testing the therapy in combination with medications that dampen the immune response. The goal is to reduce immune reactions to the therapy and allow repeat administrations. 

Chaperone therapy

One experimental approach being investigated is the use of chaperone molecules or medications that help protect and enhance the activity of the GAA enzyme that the GAA gene encodes for. Chaperones could work either with any GAA that the patient is able to produce themselves, or GAA that is administered as part of enzyme replacement therapy (ERT).

Amicus Therapeutics is using its chaperone-advanced replacement therapy (CHART) approach for the treatment of Pompe disease. The treatment uses an improved ERT called ATB200, which mimics the activity of the natural GAA enzyme, used alongside a small molecule chaperone known as AT2221 that helps protect and increase the activity of ATB200. This treatment is currently in Phase 1/2 clinical trial (NCT02675465) but is no longer recruiting participants. It is expected to be completed in June 2019.

Valerion Therapeutics had been developing Val-1221, a form of GAA combined with the proprietary delivery antibody 3E10. The therapy now will be developed by Parasail.

The GAA portion of this treatment is a new form of the enzyme, designed to break down glycogen, the complex sugar that has built up inside cells, and which the enzyme is responsible for degrading. The 3E10 antibody is intended to deliver the GAA enzyme into cells where it is needed. Val-1221 was tested in a Phase 1/2 clinical trial (NCT02898753), completed in 2020.  

Substrate reduction therapy

The idea behind substrate reduction therapy is to reduce the formation of glycogen by inhibiting two enzymes that are important in the formation of the molecule: glycogenin (GYG) and glycogen synthase (GYS). Research in mice with inhibited GYS showed that glycogen accumulation was reduced. However, GYS does also appear to be necessary for healthy heart function. Research suggests that GYS inhibition should be pursued as a treatment only if it is confined to the skeletal muscle.

Stimulation of lysosomal exocytosis

Pompe disease is categorized as a lysosomal storage disorder because glycogen builds up in cell structures called lysosomes, which contain a host of enzymes. They function as the digestive system for the cell and the enzymes they contain break down many molecules. In Pompe disease, lysosomes do not have enough GAA to break down glycogen, so it builds up inside them.

But lysosomes not only break down molecules, they sometimes fuse with the cell membrane and dump their contents out of the cell- a process called exocytosis. In the past decade, scientists discovered two transcription factors (proteins that help regulate how much of other proteins are made) that seems to induce exocytosis. In a mouse model of Pompe disease, increases in these transcription factors caused lysosomes in muscle cells to dump their glycogen, which reduced damaging glycogen build-up. This approach is still in the pre-clinical stage of development.


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