Pompe disease as a research model
The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.
“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.
Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”
Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.
“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
A robust pipeline
The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.
“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.
The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”
Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.
Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.6
Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.7 Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.
Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.8
“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”
Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.
Jennie Smith is a freelance journalist and editor specializing in medicine and health.