Battling Lysosomal Storage Diseases with ERT and SRT
Lysosomal storage diseases (LSDs) are caused by deficiencies in lysosomal enzymes needed to recycle various cell components, resulting in toxic accumulation of metabolites (Table 1). They are complex diseases that damage multiple organs and cause a diverse array of debilitating and painful symptoms; most cause neuromuscular problems and many inflict neurological damage such as mental retardation. Caused by a genetic defect, most LSDs affect infants and children, and can lead to early death if left untreated. LSDs are rare, with frequencies ranging from approximately 1 in 50,000 for Gaucher and Pompe diseases, to less than one in a million for others. The overall global incidence of all LSDs combined is estimated at approximately 1 in 5,000 (see Fuller, et al.)
There are two main approaches used to treat LSDs. The first, and more common treatment, known as enzyme replacement therapy (ERT), is to simply administer the deficient enzyme. The second, substrate reduction therapy (SRT), relies on small molecule drugs to inhibit the upstream enzyme – usually a glycosyltransferase – that produces the toxic metabolite. SRT targeting glycosyltransferases is an area where there are significant untapped opportunities for small molecule drug discovery, not only for LSDs, but also possibly for neurodegenerative diseases such as Parkinson’s disease and some types of dementia, where compromised lysosomal protein degradation leads to accumulation of pathogenic protein aggregates – more on this in a later blog.
Pompe disease was the first LSD to be described in 1932, and efforts to understand the molecular basis contributed to delineation of the glycogen metabolism pathway and discovery of the lysosome as a cellular organelle in the 1950s. Since then, more than 50 LSDs have been defined, most with a genetic defect that results in loss of a specific enzyme (see Parkinson-Lawrence et al for a comprehensive recent review).
| Disorder | Accumulated Product | Enzyme Deficiency |
| Gaucher Disease | glucocerebroside | β-glucocerebrosidase |
| Tay-Sachs disease | GM2 | β-hexosaminidase |
| Niemann-Pick disease | sphingomyelin | sphingomyelinase |
| Fabry Disease | globotriaosylceramide | α-galactosidase |
| Pompe Disease | glycogen | α-D-glucosidase |
| Mucopolysaccharidoses | glycosylaminoglycans | Various hydrolases |
| Most common LSDs showing the causative metabolite and the enzyme deficiency that causes it to accumulate to toxic levels. | ||
ERT, which might seem overly simplistic at first glance, is an extremely effective treatment as the therapeutic proteins are taken up into cells as part of the natural endocytic process. The proteins then wind up in lysosomes where the enzyme is needed. The concept was first conceived almost sixty years ago by Christian de Duve: “In our pathogenic speculations and in our therapeutic attempts, it may be well to keep in mind that any substance which is taken up intracellularly in an endocytic process is likely to end up within lysosomes. This obviously opens up many possibilities for interaction, including replacement therapy”.
Pioneering work on ERT, focused on replacement of β-glucocerebrosidase in Gaucher disease, was performed by Dr. Roscoe Brady’s group at NINDS in the early 1990’s. One of their key findings was the need to trim back carbohydrates on the β-glucocerebrosidase to expose terminal mannose residues, which targets the therapeutic protein to affected macrophages. This laid the foundation for the first ERT drug, Genzyme’s Cerezyme, used to treat Gaucher disease. Similar approaches have been used to develop ERT drugs for Pompe, Fabry and mucopolysaccharidosis. Genzyme has continued to play a major role in this area, with Shire and BioMarin developing ERT products more recently.
ERT is a highly effective treatment for many LSD patients, however due to the inability of the recombinant enzymes to cross the blood brain barrier, it fails to rectify the neurological effects experienced by many patients. SRT is an alternative strategy for these patients, and drug discovery efforts in this area are in their nascent stages. Miglustat (Actelion), a relatively non-specific glycosyltransferase inhibitor, is approved for treatment of Type I Gaucher disease, however its side effects limit its use to patients who are unable to receive ERT. It is also used to treat Neimann-Pick disease. Genzyme has developed an improved glucosylceramide synthase inhibitor, Eliglustat, that shows fewer side effects. Neither Miglustat nor Eliglustat has good CNS penetrability, and therefore they are not useful for treating Gaucher patients with neurological symptoms. There have been some limited HTS and rational design efforts focused on developing more useful glucocosylceramide synthase inhibitors, but much work remains to investigate the potential for SRTs for Gaucher disease and other LSDs with a neurological component.
Learn more about glycosyltransferase assays that helped aid in this research.
