Astellas Gene Therapies is developing AT845 for the treatment of Pompe disease.

Pompe disease is a severe, progressive, congenital neuromuscular disease. The overall incidence is estimated to be approximately 1 in 40,000 births1, although frequency and disease progression varies with age of onset, ethnicity and geography. The disease is caused by mutations in the gene that encodes the enzyme acid alpha-glucosidase, or GAA. GAA is responsible for metabolizing glycogen within the intracellular organelle known as the lysosome. Dysfunction or absence of functional GAA results in toxic accumulation of glycogen in the lysosome. Skeletal and cardiac muscles are the tissues predominantly affected by the disease.

The severity of Pompe disease symptoms and rate of progression is variable and correlated with age of symptom onset and the degree of enzyme deficiency. Infantile-onset Pompe disease, the most severe form of the disease, accounts for approximately one quarter of all affected patients. Those with infantile-onset Pompe disease are usually diagnosed in the first few months of life due to the severe presentation associated with total or near-total absence of GAA activity. These infants usually present with feeding difficulties, failure to thrive, hypotonia, progressive weakness, respiratory distress, severe enlargement of the tongue and thickening of the heart muscle. If left untreated, these children usually do not live past the first year of life. Those with late-onset Pompe disease typically have enzyme activity levels ranging from 1 to 40 percent of normal and usually have symptoms such as progressive muscle weakness leading to decreased motor function and respiratory failure2. The life expectancy of late-onset Pompe patients can vary widely but the disease burden can have a significant impact on the quality of life for those patients. Newborn-screening programs have been instrumental in the early diagnosis and treatment of Pompe disease, but such programs have not yet been widely implemented worldwide.

The only approved treatment for Pompe disease is enzyme replacement therapy, or ERT, which is a chronic treatment typically delivered in bi-weekly intravenous infusions. Despite the availability of ERT, significant unmet medical need still persists, which is primarily due to the inability of ERT to penetrate key tissues affected by the disease and to the immunogenicity of ERT.

Astellas Gene Therapies is developing AT845, a novel gene replacement investigational therapy to address the recognized limitations of ERT by targeting the muscle tissues, the primary tissue affected in Pompe disease. AT845 utilizes a muscle-directed approach with an AAV8 capsid serotype that is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle. This best-in-class approach stands in contrast to approved enzyme replacement therapies and liver-directed investigational gene therapy candidates that rely solely on tissue uptake of GAA from plasma.

Pompe Disease

Pompe disease is caused by mutations in the gene that encodes the enzyme acid alpha-glucosidase (GAA) responsible for breaking down glycogen within the lysosome. Deficiency of GAA leads to glycogen build-up and tissue and organ damage. The overall incidence is estimated to be approximately 1 in 40,000 births1. Pompe disease spans a continuum of disease spectrum. The adult late-onset form is characterized by slow progressive myopathy primarily involving skeletal muscle while the infantile form is rapidly progressing and is characterized by cardiomegaly, hepatomegaly, weakness and hypotonia. If left untreated, many children with infantile onset Pompe disease, usually do not live past the first year of life.

Our approach: we are developing an AAV vector to deliver a functional GAA gene to express GAA directly in muscle cells. This approach differs from approved enzyme replacement therapy (ERT) and liver-directed investigational gene therapy candidates that must overcome the challenges of muscle GAA uptake from plasma.


  1. Kishnani et al. 2006 Pompe disease diagnosis and management guideline. Version 1. Genet Med. 8(5): 267–288.
  2. Kishnani and Howell 2004 Pompe disease in infants and children. J of Pediatrics 144: S35-S43.