Enzyme replacement therapy is used to treat lysosomal storage diseases in which there is a pathological accumulation of degradation products in the lysosomes of cells due to a lack of enzymes. The enzymes missing due to genetic defects are compensated for in the form of regular intravenous infusions. Because the infused synthetic enzymes cannot cross the blood–brain barrier due to their molecular size, the therapy only strikes in lysosomal storage diseases that do not affect the central nervous system.
What is enzyme replacement therapy?
Enzyme replacement therapy is used to replace missing endogenous enzymes with synthetically produced enzymes. Lysosomes are special cell organelles in which foreign and endogenous substances are broken down and partially recycled. Specific hydrolyzing enzymes are required for the degradation and transport of the substances. These are proteases, nucleases, lipases and transporters. Due to a number of known genetic defects, certain enzymes may fail, causing some degradation products to accumulate in pathological amounts in the lysosomes and to build up until they reach the extracellular matrix, i.e. the intercellular spaces, in an uncontrolled manner. All genetic defects that lead to a failure of at least one necessary hydrolase are grouped under the term lysosomal storage disease. Enzyme replacement therapy (ERT) is used to replace the missing endogenous enzymes with synthetically produced enzymes. Because hydrolases consist of relatively large molecules, they cannot be absorbed by the intestine without first being broken down and inactivated, so they can only be administered by intravenous infusion. However, the size of the enzyme molecules also prevents them from crossing the blood–brain barrier, so the therapy can only be effective for lysosomal storage diseases that do not affect the central nervous system (CNS).
Function, effects, and targets
More than 50 different lysosomal metabolic disorders are known, each of which is due to a monogenetic defect. The lysosomal storage diseases can be divided into seven different classes depending on the excessively stored substances based on the enzyme defect present. Mucopolysaccharidoses and oligosaccharidoses are primarily candidates for ERT. The aim of ERT is always to compensate for the specific enzyme deficiency by means of the artificially supplied enzymes in order to achieve a halt to the disease or at least a milder course. Specifically, replacement enzymes are available for the following lysosomal storage diseases:
- Gaucher disease
- Pompe’s disease
- Fabry disease
- Hurler-Pfaundler syndrome (mucopolysaccharidosis I)
- Hunter’s disease (mucopolysaccharidosis II)
– Maroteaux-Lamy syndrome (mucopolysaccharidosis VI)
– Niemann-Pick B
Gaucher disease is the most common lysosomal storage disease. It occurs in three different variants, of which two courses also affect the nervous system. In the non-neuropathic form, the spleen is mainly affected, which becomes severely enlarged and leads to secondary damage such as anemia and damage to the bone marrow. Typical symptoms include bone and joint pain and circulatory problems. The acute neuropathic variant of the disease shows a severe course and offers little chance of survival beyond the first two years of life. Pompe disease is caused by a deficiency of the enzyme alpha-1,4-glucosidase, which is involved in a number of metabolic processes. Pompe disease results in enormous heart enlargement (cardiomegaly) and heart failure. There are early, severe, courses that occur in the first months of life as well as milder forms that occur later in life. Fabry disease is caused by an X-linked genetic defect, so that only boys and men can be affected by the storage disease. The disease usually leads to symptoms in advanced childhood, including attacks of pain, keratomas of the skin, kidney problems and heart muscle damage. Deficiency of the enzyme alpha-galactosidase A leads to a buildup of ceramide trihexoside, which is causative in triggering symptoms that may also affect the autonomic nervous system. It is not uncommon for a heart attack, renal infarction or even a stroke to develop as a result of the damage.Hurler-Pfaundler syndrome is also known as mucopolysaccharidosis, type I, and results from a disorder of glycosamine glycan metabolism. The disease is associated with a variety of symptoms including severe mental retardation and severe skeletal changes. The course of the disease is severe, such that the average life expectancy is reported to be 11 to 14 years. Hunter’s disease corresponds to mucopolysaccharidosis, type 2 and, like Hurler’s disease, is caused by an X-linked defect. The disease is characterized by varying severity from onset in early childhood to mild onset in adult males. Due to mostly occurring cardiac symptoms such as valvular defects and myocardial problems, life expectancy ranges from normal to slightly limited. Maroteaux-Lamy syndrome (MPS VI) belongs to the mucopolysaccharidoses, which are inherited in an autosomal recessive manner because the triggering gene defect is not located on the X chromosome. The disease is very rare, with one case per 455,000 births. Mild and more severe forms of the disease are known. Symptomatic features include an enlarged liver and spleen, carpal tunnel syndrome, and heart valve abnormalities. Niemann-Pick B is a sphingomyelin lipidosis that belongs to the lysosomal storage diseases and is caused by a gene defect on chromosome 11. While type B of the disease mainly affects the liver and spleen, type A has significant additional neuronal problems.
Risks, side effects, and dangers
Because many of the lysosomal storage diseases treatable by enzyme replacement therapy take a severe course if left untreated, with a corresponding increase in mortality, the greatest risk in ERT is that the chosen replacement enzyme will not work or will work too weakly. Another risk lies less in the therapy itself than in the fact that the underlying disease is detected too late, so that although ERT can stop the disease in its course, the damage already caused cannot be reversed. About one in two patients treated reacts temporarily to the infusions with symptoms such as fever and chills. The causes of this are not yet fully understood. Some patients react by forming antibodies, and there are known cases in which patients have reacted with skin rashes and bronchospasm.
