Enzyme replacement therapy

Enzyme replacement therapy (ERT or ERT engl. Enzymes Replacement Therapy ) is a therapeutic procedure used to treat enzyme deficiencies in lysosomal storage diseases. Patients are thereby fed synthetic enzymes by infusion or injection.

The enzyme defect in the patient may be caused by a missing or defective enzyme. The treatment is life-long at regular intervals. In ERT, the disease itself is not treated or cured, but it can be used to treat symptoms of the disease.

Principle of operation

Through genetic enzyme defects, patients with lysosomal storage diseases specific macromolecules in some body cells no longer break down sufficiently. Thus, the non -degradable macromolecules accumulate in the cell, where they can cause damage to the cells and various organs constructed therefrom.

Patients affected by the enzyme defect obtained by means of an infusion of the missing enzyme. The cells of various organs take a receptor-mediated endocytosis to the enzyme in the lysosome, where they take on the catalytic function of the lack of endogenous enzymes.

Some of the patients received enzyme replacement therapy developed antibodies against the infused enzyme. However, this does not affect the therapeutic effect of the therapy because most antibody are obviously not able to neutralize the enzyme infused. The titer of antibodies decreases during the further course of therapy again, which can be explained by the formation of an immunological tolerance.

Limitations of enzyme replacement therapy

With enzyme replacement therapy only the lysosomal storage diseases can be treated, do not cause central nervous system disorders. The reason for this is that the intravenously administered enzymes due to their size does not cross the blood -brain barrier and thus can not reach the brain. For lysosomal storage diseases in which the brain is affected by the enzyme defect of the storage of undegraded metabolites, therapy - which relates to the cerebral aspects - no effect. This is true for most lysosomal storage diseases. Here, the substrate reduction therapy better therapeutic perspectives. Overcoming the blood -brain barrier by transcytosis is a possible future way to apply the enzyme replacement therapy for lysosomal storage diseases cerebral. These possibilities are still far away still in its infancy and of an authorized medicinal product.

Drug production

The enzymes used in enzyme replacement therapy are produced by recombinant DNA technology ( " GMO "). This can be used for both human, murine, bovine, and CHO cell lines.

Costs

The cost of enzyme replacement therapy are extremely high. For example, the annual cost of treatment for patients with Fabry disease are at about 200,000 euros per patient. In the case of ERT of Gaucher disease, the cost in the range of 375,000 and 700,000 euros per patient per year, alone for the drug. In Germany, the health insurance companies cover the cost of treatment when a firm diagnosis is made. In Austria, the assumption of the costs for each patient must be individually negotiated with the cash. The reason for the high cost of enzyme replacement therapy is the one in the cost, on the other hand, especially in the small number of patients for an approved enzyme replacement therapy. The high development and approval costs are spread over a fairly small number of patients. In Austria, for example, the number of treated patients in the double- digit range.

Examples of therapy

Gaucher disease

The Gaucher disease is the most common lysosomal storage disease with a prevalence of about 1:200,000. The subjects in the disease enzyme glucocerebrosidase was first isolated in 1973 and infused a child. This was the world's first enzyme replacement therapy. In the following years, the enzyme was extracted from human placentas and used under the brand name Ceredase for enzyme replacement therapy in Gaucher's disease. Since the late 1990s, a recombinantly produced drug ( Cerezyme ) is permitted.

Hurler's syndrome Pfaundler MPS type I

On April 30, 2003, an enzyme replacement therapy for mucopolysaccharidosis I ( Hurler syndrome Pfaundler ) was approved in the United States. In Europe, the approval was granted on 10 June 2003. Patients enzyme iduronidase artificially produced is thereby supplied by infusion. The enzyme was first established in 1992 biotechnologically. The patients received weekly infusions. In various studies, there were significant improvements in the clinical symptoms. In the treated patients after six weeks could be reduced, sometimes even a normalization of the size of the liver and spleen was observed. The concentrations of mucopolysaccharides in the urine took a few weeks off strong. In many of the patients an increase in body weight, as well as a growth spurt before puberty was observed.

Hunter syndrome MPS type II

In January 2007, the European Commission has the enzyme Idursulfase ( iduronate -2-sulfatase ) ( mucopolysaccharidosis type II) approved for the treatment of Hunter syndrome.

Maroteaux -Lamy syndrome MPS Type VI

Arylsulfatase B ( drug Galsulfase, trade name Naglazyme ) was approved in the U.S. and on January 30, 2006 in Europe for the treatment of Maroteaux -Lamy syndrome ( mucopolysaccharidosis type VI) on 31 March 2005.

Pompe disease

Since April 2006, α - glucosidase ( INN = Alglucosidase alpha, brand name Myozyme ) in Europe is approved for the treatment of Pompe disease. In 1999, the transgenic enzyme was first obtained from rabbit milk. Meanwhile, it is produced from CHO cell lines recombinantly. It is administered to the patient intravenously every two weeks.