CRANBURY, N.J.—Pompe disease, a fatal neuromuscular and motorneuron disorder, affects 5,000 to 10,000 people worldwide. Caused by deficiency of the enzyme acid alpha-glucosidase (GAA), the inherited lysosomal storage disorder can lead to the accumulation of glycogen in cells.
The debilitating disease is characterized by severe muscle weakness that worsens over time. Pompe disease ranges from a rapidly fatal infantile form significantly impacting heart function to a more slowly progressive, late-onset form primarily affecting skeletal muscle. Respiratory and cardiac failure are the leading causes of morbidity and mortality.
Amicus Therapeutics, a biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare metabolic diseases, is collaborating with the Gene Therapy Program of the Perelman School of Medicine at the University of Pennsylvania (Penn) to develop a novel gene therapy for Pompe disease. The proposed therapy combines the Amicus protein-engineering and glycobiology expertise with Penn’s adeno associated virus (AAV) gene transfer technologies. Amicus announced initial preclinical data from its investigational AAV gene therapy program for Pompe disease in mice at a poster session entitled “Development of a Novel Gene Therapy for Pompe Disease: Engineered Acid Alpha-Glucosidase Transgene for Improved Expression and Muscle Targeting” at the American Society of Gene & Cell Therapy 22nd Annual Meeting in Washington, D.C.
As explained in the poster session, the current standard of care, enzyme replacement therapy (ERT), is limited in improving muscle function and unable to cross the blood-brain-barrier, causing progressive neurologic deterioration in long-term survivors of classic infantile Pompe disease. ERT using recombinant human GAA (rhGAA) delivered every other week by intravenous infusion is the only approved treatment available for Pompe disease. To be effective, rhGAA must be internalized in target muscle cells and delivered to lysosomes at clinically relevant doses. Maintaining both efficacy and safety has proven difficult.
According to Dr. Hung Do, chief science officer of Amicus, “These very important preclinical results validate our capabilities to develop engineered GAA proteins that can efficiently cross-correct target cells and tissues via a gene replacement therapy for Pompe disease. This approach may be applicable to other lysosomal disorders as we continue to combine our Amicus protein engineering expertise, together with Penn’s vector engineering expertise, to develop novel gene therapies.”
The Amicus/Penn Pompe hGAA AAV gene therapy program builds upon the protein engineering and manufacturing expertise used to successfully develop AT-GAA, Amicus’s late-stage enzyme replacement therapy (ERT)-chaperone treatment paradigm. It demonstrated more uniform cellular uptake and lysosomal targeting compared to natural hGAA AAV gene therapy. In addition, the engineered hGAA AAV gene therapy demonstrated robust glycogen reduction in all key tissues in Pompe disease that were examined. In the central nervous system, the engineered hGAA AAV gene therapy reduced glycogen significantly in neuronal cells, indicating that it could be an effective method of addressing neuronal aspects of Pompe disease. Conversely, natural hGAA AAV gene therapy did not reduce glycogen in neuronal cells.
Thus, initial findings validate the Amicus/Penn collaboration and the potential of this platform to enhance protein targeting across multiple lysosomal disorders. Further preclinical studies to evaluate this engineered hGAA with various doses and routes of AAV administration are underway.
“Developing a potential cure for Pompe has been a personal and professional goal for many years,” said John F. Crowley, chairman and CEO of Amicus. “These data are profound, and it is extremely rewarding to see these preclinical results that show our Amicus-engineered GAA is optimized for uptake into target tissues and gets to the right cellular compartments, especially in the central nervous system. These data also provide preliminary and compelling evidence that the Amicus technology to design constructs that enhance protein targeting may be a significant platform for multiple lysosomal disorders.”
Crowley noted that the company’s preclinical studies were progressing well ahead of schedule. The company expects to select a clinical candidate in 2019 to move forward into IND-enabling studies. Amicus is also collaborating with Penn on AAV gene therapies for Fabry disease, CDKL5 deficiency disorder and another rare metabolic disease. The agreement provides funding to Penn to advance the preclinical research programs and to license certain technologies invented under the funded research collaboration.
Dr. James M. Wilson, professor of medicine and pediatrics at the Perelman School of Medicine at Penn, summarized, “Amicus focuses on proteins and protein engineering, with a track record in the lysosomal disorders, which are critically important to developing AAV gene therapies that can safely and effectively address these diseases. These initial preclinical results are a significant step in highlighting our collaboration to rapidly advance gene therapies into the clinic for patients with urgent unmet needs. These results demonstrate that the Amicus gene therapy that we have jointly developed has the potential to address both the neuromuscular as well as the motor neuron aspects of Pompe disease.”