Enzyme replacement therapy

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The enzyme replacement therapy ( ERT or ERT of Engl. Enzyme Replacement Therapy ) is a therapeutic method for the treatment of enzyme defects in lysosomal storage diseases . Synthetic enzymes are administered to the patient via infusion or injection .

The enzyme defect in the patient can be caused by a missing or defective enzyme. Treatment is carried out at regular intervals for life. With ERT, the disease itself is not treated or cured , but the symptoms of the disease are treated.

Working principle

Genetically determined enzyme defects mean that patients with lysosomal storage diseases can no longer sufficiently break down certain macromolecules in some body cells . As a result, the non-degradable macromolecules accumulate in the cell, where they can damage the cells and various organs built from them.

The patients affected by the enzyme defect receive the missing enzyme by means of an infusion . The cells of various organs take up the enzyme in the lysosome via a receptor-mediated endocytosis , where they take over the catalytic function of the missing endogenous enzymes.

Some of the patients who receive enzyme replacement therapy develop antibodies against the infused enzyme. However, this does not affect the therapeutic effect of the therapy, since most antibodies are obviously not able to neutralize the infused enzyme. The titer of antibodies increases in the course of therapy and then, what with the formation of an immunological tolerance can be explained.

Limitations of enzyme replacement therapy

Enzyme replacement therapy can only be used to treat lysosomal storage diseases that do not cause any central nervous disorders. The reason for this is that the intravenously administered enzymes, due to their size, cannot cross the blood-brain barrier and thus cannot get into the brain. For lysosomal storage diseases, in which the brain is affected by the enzyme defect from the storage of the metabolic products that have not been broken down, the therapy - as far as the cerebral aspects are concerned - is ineffective. This is true of most lysosomal storage diseases. Substrate reduction therapy offers better therapeutic prospects here. Overcoming the blood-brain barrier by means of transcytosis is a possible future way of using enzyme replacement therapy for cerebral lysosomal storage diseases. These possibilities are still at the beginning of their development and are still a long way from being an approved drug.

Active ingredient production

The enzymes used in enzyme replacement therapy are produced using recombinant DNA technology ("genetic engineering"). Both human , murine , bovine and CHO cell lines can be used.

costs

The cost of enzyme replacement therapy is extremely high. For example, the annual treatment costs for patients with Fabry's disease are around 200,000 euros per patient. In the case of ERT for Gaucher's disease, the costs are in the range of 375,000 and 700,000 euros per year and patient, just for the drug. In Germany, the health insurance companies cover the therapy costs if a reliable diagnosis has been made. In Austria, the assumption of the costs for each patient must be negotiated individually with the health insurance companies. The reasons for the high costs of enzyme replacement therapy are, on the one hand, the manufacturing costs, and, on the other hand, primarily the low number of patients for an approved enzyme replacement therapy. The high development and approval costs are spread over a relatively small number of patients. In Austria, for example, the number of patients treated is in the double-digit range.

Therapy examples

Gaucher's disease

The Gaucher disease is a prevalence of about 1: 200,000 is the most common lysosomal storage disease. The enzyme glucocerebrosidase , which is affected by the disease , was first isolated in 1973 and infused into a child . This was the world's first enzyme replacement therapy. In the following years, the enzyme was obtained from human placentas and used under the brand name Ceredase for enzyme replacement therapy in Gaucher's disease. Recombinantly produced active ingredients have been approved since the late 1990s: Imiglucerase (trade name Cerezyme) and Velaglucerase (trade name Vpriv).

Hurler-Pfaundler syndrome MPS type I

On April 30, 2003, enzyme replacement therapy for the treatment of mucopolysaccharidosis type I ( Hurler-Pfaundler syndrome ) was approved in the USA . In Europe, approval was granted on June 10, 2003. The patient is infused with the artificially produced enzyme iduronidase . The enzyme was first produced biotechnologically in 1992. The patients receive weekly infusions. There were significant improvements in clinical symptoms in various studies. In the treated patients, a reduction, in some cases even a normalization of the size of the liver and spleen, was observed after six weeks . The concentration of mucopolysaccharides in the urine decreased sharply after a few weeks. In many of the patients treated, an increase in body weight and a growth spurt before puberty was observed.

Hunter's disease MPS type II

In January 2007 the European Commission approved the enzyme idursulfase ( iduronate-2-sulfatase ) for the treatment of Hunter's disease (mucopolysaccharidosis type II).

Maroteaux-Lamy syndrome MPS type VI

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

Pompe disease

Since April 2006, α-glucosidase ( INN = alglucosidase alfa , brand name Myozyme ) has been approved in Europe for the treatment of Pompe disease . The transgenic enzyme was first obtained from rabbit milk in 1999. It is now produced recombinantly from CHO cell lines. It is given intravenously to patients every two weeks.

Individual evidence

  1. ↑ a b J. Blanz and P. Saftig: Enzyme replacement therapy in the lysosomal storage disease alpha-mannosidosis. In: DKFZ 11/12, 2006, pp. 42-49
  2. ^ GM Pastores: Miglustat: Substrate Reduction Therapy for Lysosomal Storage Disorders Associated with Primary Central Nervous System Involvement. ( Memento from June 16, 2010 in the Internet Archive ) (PDF; 75 kB) In: Recent Patents on CNS Drug Discovery. 1, 2006, pp. 77-82. PMID 18221193
  3. ↑ M. Rosenberg et al .: Immunosurveillance of alglucerase enzyme therapy for Gaucher patients: induction of humoral tolerance in seroconverted patients after repeat administration. In: Blood 93, 1999, pp. 2081-2088.
  4. ^ HJ Galla and V. Gieselmann: The blood-brain barrier and the therapy of lysosomal diseases. In: BIOspektrum 5, 2008, pp. 460–464.
  5. ↑ A. Urayama et al .: Developmentally regulated mannose 6-phosphate receptormediated transport of a lysosomal enzyme across the bloodbrain barrier. In: PNAS 101, 2004, pp. 12658-12663. PMID 15314220
  6. ↑ A. Klement: Gaucher disease and Zavesca® ( Memento from September 20, 2008 in the Internet Archive ) In: ÖAZ 2, 2004, p. 5.
  7. ↑ a b D. Boerner: Clinical, laboratory chemical and radiological long-term course of the individualized enzyme replacement therapy for Gaucher disease. Dissertation, University of Düsseldorf, 2002. urn : nbn: de: hbz: 061-20020128-000427-7
  8. ^ A b F. Breunig and RM Schaefer: Fabry disease - New perspectives through enzyme replacement therapy. Pp. 50-66
  9. ↑ ORF.at: Enzyme replacement therapy ( memento from January 17, 2010 in the Internet Archive ) viewed on January 8, 2008
  10. ↑ P. Pentchev and S. Hibbert: Isolation and characterization of glucocerebrosidase from human placental tissue. In: J Biol Chem 248, 1973, pp. 5256-5261. PMID 4768898
  11. ↑ P. Pentchev include: Replacement therapy for inherited enzyme deficiency: sustained clearance of accumulated glucocerebroside in Gaucher's disease Following infusion of purified glucocerebrosidase. In: J Mol Med 1, 1975, pp. 73-78.
  12. ^ RO Brady et al.: Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher's disease. In: NEJM 291, 1974, pp. 989-993. PMID 4415565
  13. ↑ Enzyme Replacement Therapy (EET) at MPS I ( Memento from January 26, 2010 in the Internet Archive ) viewed on January 9, 2009
  14. ↑ unknown: Enzyme replacement therapy - a great hope for patients with mucopolysaccharidosis type I. In: JournalMed edition 6/2004
  15. ↑ C. Becker: First enzyme replacement therapy for mucopolysaccharidosis I In: Pharmazeutische Zeitung 8, 2003
  16. ↑ unknown: European Commission approves enzyme replacement therapy for Hunter's disease. dated January 12, 2007
  17. Jump up ↑ Hunter Disease - First enzyme replacement therapy approved January 12, 2007
  18. ^ Society for Mukopolysaccharidosen eV: Type VI: Causal Therapies
  19. ↑ M. Beck: Galsufase: Enzyme Replacement Therapy for Mucopolysaccharidosis Type VI (Maroteaux Lamy). In: Therapy 3, 2006, pp. 9-17.
  20. ↑ T. Merk et al.: Severe chronic respiratory insufficiency in adult glycogenosis type II (Pompe disease). In: Medical Clinic 102, 2007, pp. 570-573. doi : 10.1007 / s00063-007-1070-z
  21. ↑ Pompe portal: Enzyme replacement therapy and Myozyme ( Memento of the original from April 7, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.pompe-portal.de

literature

  • C. Haase: Enzyme replacement therapy for congenital metabolic diseases. In: Kinder- und Jugendmedizin 6, 2006, pp. 241–248.
  • NW Barton et al .: Replacement therapy for inherited enzyme deficiency - macrophage-targeted glucocerebrosidase for Gaucher's disease. In: NEJM 324, 1991, pp. 1464-1470. PMID 2023606
  • P. Daloze et al.: Replacement therapy for inherited enzyme deficiency: liver orthotopic transplantation in Niemann-Pick disease type A. In: Am J Med Genet 1, 1977, pp. 229-239. PMID 345809
  • RO Brady et al: Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. In: NEJM 289, 1973, pp. 9-14. PMID 4196713

Web links