Lysosomal Storage Diseases  are a class of more than 40 rare genetic disorders, each caused by a deficiency in a specific lysosomal enzyme. Lysosomes are enzyme-laden compartments within cells where macromolecules are disassembled and their component parts recycled. Each lysosomal enzyme performs a specific step in the disassembly process. The absence of any one of these enzymes can cause the toxic accumulation of undigested substrate, thereby impairing cellular and tissue function. Individuals afflicted with LSDs can die at an early age or suffer from a painfully debilitating disease for several decades. 

Among treatments for LSDs, replacement of the missing enzyme has proved to work the best. For enzyme replacement therapy to be effective, the therapeutic enzyme must be delivered to the appropriate cells in tissues where the storage defect is manifest. Delivery of lysosomal enzymes to cells in target tissues has been accomplished by using carbohydrate on the protein surface to engage specific receptors on the surface of the target cells. For example, glucocerebrosidase, the enzyme deficient in Gaucher disease, can be delivered specifically to macrophage by engaging the mannose receptor with its carbohydrate. The specificity of this delivery is due to the fact that the mannose receptor is present only on cells of the reticuloendothelial system. 

Unlike Gaucher disease, many other lysosomal storage diseases exhibit storage defects in other cell types. In these cases, targeting the mannose receptor is not an effective approach for delivery. Instead, the strategy for delivery to these cell types has been to use mannose-6-phosphate (M6P) containing carbohydrate to engage the M6P receptor present on a wide variety of cell types. M6P-mediated delivery can be achieved in clinically important tissues like heart, kidney, lung, muscle and bone. For example, the M6P component of the carbohydrate on Fabrazyme, one approved LSD therapy, permits it to bind to the M6P receptor on the surface of interstitial endothelial capillary cells of the kidney, the clinically important cells that were monitored as a surrogate endpoint in the Phase 3 clinical trial of Fabrazyme. Despite this success, most of the infused dose of a therapeutic enzyme such as Fabrazyme is removed from the bloodstream before it can reach its target because its carbohydrate still binds to the highly abundant mannose receptor on the surface of macrophage in the liver and spleen. As a result, the infused enzyme is cleared from the bloodstream quite rapidly. This greatly limits the amount of enzyme available for delivery to target cells and tissues.

Currently, there are only four enzyme–replacement therapeutics approved for the treatment of three of the more than 40 known LSDs. The drugs currently approved for the treatment of LSDs suffer from several inadequacies. Perhaps most importantly, some LSD patients who receive conventional enzyme-replacement therapies suffer from certain pathologies (e.g., bone abnormalities) because inadequate amounts of enzyme are delivered to critical tissues. In addition, patients require large and frequent intravenous doses of these drugs. As a result, LSD patients on these therapies must visit a clinic several times a month to be infused with the drugs for several hours at a time. Also, current LSD drugs are expensive to manufacture, in part due to the need for proper glycosylation of the enzymes. 

Pompe Disease is a rare, progressive and often fatal disease that was first described in 1932 by the Dutch pathologist J.C. Pompe, who documented the case of a seven month old girl who died suddenly from a disease associated with the accumulation of glycogen in many tissues.1  In 1954, Nobel laureate G.T. Cori identified the existence of a class of diseases caused by impaired glycogen metabolism and designated Pompe disease as Glycogen Storage Disease, type II (GSD-II).2  In 1963, H.G. Hers linked the basis of Pompe disease to an inherited absence or shortage of enzymes present within the compartment of the cell known as the lysosome, making Pompe disease the first to be classified as an LSD.3  Between 1961 and 1970, several investigators published the first reports of a late-onset form of the disease. The first clinical use of purified human placental GAA was reported in 1973. Several problems hindered the use of placental GAA, including its low-uptake and the limitations in clinical trial design (trial duration and amount of GAA administered).4  In 1979, Hirschhorn et al. noted that the gene responsible for Pompe disease was traced to chromosome 17, which provided the basis for further understanding of the pathophysiology and genetics of this disorder.5  Subsequent cloning of the GAA gene made it feasible to produce recombinant human GAA. Clinical trials investigating the efficacy of recombinant human GAA in Pompe disease were initiated in 1999, and Genzyme commercially launched Myozyme as the first treatment for Pompe disease in 2006.6 

Pompe disease can affect infants, children and adults. Symptoms may first appear during the initial months after birth or at any time during adolescence or adulthood. In some cases, symptoms may first appear in individuals in their 60s. The disease is often broadly divided or classified into two groups, a rapidly fatal infant-onset form with severe cardiac and respiratory involvement and a more slowly progressive late-onset form without cardiac involvement, primarily affecting skeletal muscle.7  Progressive muscle weakness is a prominent characteristic in all forms of Pompe disease, and the muscles most often affected are those used for breathing and mobility.

Infant-onset Pompe disease typically presents rapidly with initial observations of profound hypotonia, muscle weakness, and a “floppy baby” appearance. The hallmark sign of infant-onset Pompe disease is marked cardiomegaly, or an enlarged heart, although feeding difficulties and respiratory problems may manifest at early stages as well. Death from cardio-respiratory failure usually occurs by 12 months of age.

Late-onset Pompe disease can present anytime during early childhood until adulthood with progressive muscle weakness and/or respiratory insufficiency. Morbidity and life expectancy are difficult to predict in late-onset patients as the course of the disease varies widely. Typically, death results from respiratory failure.

Pompe disease is estimated to affect between 5,000 and 10,000 individuals worldwide. While epidemiologic data is scarce due to the rarity and lack of information, current estimates put the overall disease incidence at one in 40,000 live births. This figure is supported by two studies, one conducted in the Netherlands (n=3,000) and the other in New York (n=928).8  Additionally, studies conducted in the Dutch population evaluating the frequency of genetic mutations have obtained reliable estimates of the incidence of both infant-onset and late-onset Pompe disease by calculating the frequency of known GAA mutations.9  Overall, the Dutch study, taken from 3,000 newborns, confirmed similar findings to estimates derived from a U.S.-based study population published by researchers in New York. Additionally, other studies have shown that incidence may vary across ethnic groups, with the highest incidence of infantile-onset disease occurring in African American and Chinese populations.10  The incidence of Pompe disease is summarized below.11

• Infantile Onset - 1/138,000 Births (1/43,000 to 1/536,000)
• Late Onset - 1/57,000 Births (1/27,000 to 1/128,000)
• All Pompe - 1/40,000 Births (1/18,000 to 1/100,000)

Pompe Disease Pathogenesis and Diagnosis

Glycogen, the basic form of glucose storage in cells, is abundantly present in muscle and liver tissue. When glucose is needed, glycogen is hydrolyzed via complex enzymatic pathways in the cytoplasm. During times of cellular turnover, glycogen is taken up by the lysosome and broken down into glucose that can be excreted and recycled. GAA is responsible for metabolizing lysosomal glycogen. Under normal circumstances, either the body converts the glycogen to energy or the lysosome breaks down the excess glycogen. In people with Pompe disease, there is a defect in the gene encoding GAA and the enzyme is either missing or in short supply. As a result, a massive accumulation of glycogen occurs in the lysosome, which leads to lysosomal distention, with glycogen dispersion into the cytoplasm, cellular damage, and eventual organ dysfunction. As the disease progresses, muscle function, especially skeletal and heart muscles, become progressively weaker and eventually fail. The pathogenesis of Pompe disease is shown in the figure below.12

The diagnosis of Pompe disease often presents a dilemma due to the disease’s rarity and the relatively wide range of symptoms that may only in aggregate lead to suspicion of Pompe disease. While the infant-onset form may be easier to diagnose because of its rapid progression and pronounced signs, symptoms can develop slowly and may not show up in the same pattern. Additionally, many physicians may not have encountered Pompe disease previously.

Nevertheless, while diagnosis is challenging, there are various methods to aid in narrowing down the diagnostic investigation from the clinical observations. The most common method used to confirm a diagnosis of the disease is an enzyme assay. Through the measurement of GAA enzyme activity in cultured skin fibroblasts or muscle, Pompe disease can be identified definitively. Alternatively, healthcare providers may diagnose Pompe disease through the measurement of GAA activity in dried blood spots. Dried blood spot testing is a less-invasive method than assays in cultured skin fibroblasts or muscle biopsies. The less-invasive method provides a faster result and is a more applicable option for screening of newborn babies.

In 2007, Illinois became the first U.S state to add newborn screening of LSDs and passed a Senate bill that added five LSDs, including Pompe disease to the standard screening program. Additionally in 2007, Washington state initiated a pilot program to evaluate newborn screening for Pompe disease. If more widely adopted, infant screening for Pompe disease could accelerate the timing of diagnosis and potentially increase the number of positive diagnoses. Although there are many benefits to screening for LSDs, issues need to be addressed prior to the widespread adoption of newborn screening for Pompe disease. Specific concerns remain with regards to protocol for secondary testing, methods of screening and management of late-onset patients. In general, widespread adoption of newborn screening for Pompe disease would result in increased demand for enzyme replacement therapies as infantile Pompe disease patients currently go six to eight months without treatment before being diagnosed.