Substrate reduction therapy

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The substrate reduction therapy ( SRT , engl. : Substrate reduction therapy ) is a therapeutic method for the treatment of lysosomal storage diseases .

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. In substrate reduction therapy, patients receive orally available drugs that are intended to prevent ( inhibit ) the formation of the non-degradable substance . This leads to a reduction in the number of non-degradable substances in the cell. In the case of small molecules ( small molecules ), these active ingredients are - in contrast to the enzymes in the enzyme replacement therapy - the able blood-brain barrier to overcome. This can also be used to treat cerebral forms of lysosomal storage diseases. With substrate reduction therapy - as with enzyme replacement therapy - the disease itself is not treated or cured, but the symptoms of the disease are treated. Patients must take the medication at regular intervals for life.

Problem

The development of suitable active ingredients for enzyme replacement therapy is extremely difficult. On the one hand, due to the sometimes very low prevalence of lysosomal storage diseases, there are only very few patients for the implementation of clinical studies and, on the other hand, the requirements relating to drug safety over very long periods of use are important. The drugs are to be taken for life. Due to the rarity of the diseases, the market for a developed drug is extremely small. The development costs are thus distributed over a small number of patients, which in turn results in very high treatment costs per patient.

Therapy example

Miglustat (chemically: N-butyl-deoxygluconojirimycin; also known as N-butyldeoxynojirimycin, NB-DNJ, brand name Zavesca® ( CAS 72599-27-0)), a glycosyltransferase inhibitor is used for oral treatment of mild to moderate type 1 Gaucher Disease Approved (US since July 31, 2003). However, it may only be used in patients for whom enzyme replacement therapy is not an option. It is approved for this indication in the European Union, the USA, Canada, Switzerland, Brazil, Australia, Turkey and Israel. The reason for the restriction of the indication is the weaker effectiveness (compared to enzyme replacement therapy) and the considerable side effects.

Miglustat inhibits the enzyme glycosyltransferase , which in the first step of glycosphingolipid synthesis catalyzes the formation of glucocerebroside - the storage substance in Gaucher's disease. Miglustat was approved in the European Union for the treatment of Niemann-Pick type C disease in 2009.

Individual evidence

  1. ↑ 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. ↑ unknown: Miglustat (Zavesca®) receives positive recommendation from the European Committee for Medicinal Products for Human Use for the indication Niemann-Pick type C.  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. dated December 29, 2008@1@ 2Template: Dead Link / www.direktbroker.de  
  4. ↑ a b S. Dahl: Gaucher disease - drug therapy of a rare metabolic disease (PDF; 196 kB) In: Apothekenmagazin 7, 2004, pp. 168–175.
  5. ↑ T. Cox et al.: Novel oral treatment of Gaucher's disease with N-butyldeoxyjirinomycin (OGT 918) to decrease substrate biosynthesis. In: The Lancet 355, 2000, pp. 1481-1485.
  6. ↑ Orphan Drug: Authorization for Miglustat extended. IN: Pharmaceutical Newspaper. 6, 2009.

literature

Reference books

  • M. Beck: Genetically determined metabolic diseases. Deutscher Ärzteverlag, 2006, ISBN 3-769-10523-0
  • AH Futerman and A. Zimran: Gaucher Disease CRC Press, 2006, ISBN 0-849-33816-6

Reviews

  • S. Bruni et al: Update on treatment of lysosomal storage diseases. In: Acta Myol 26, 2007, pp. 87-92. PMID 17915580
  • FM Platt and M. Jeyakumar: Substrate reduction therapy. In: Acta Pediatr Suppl 457, 2008, pp. 88-93. PMID 18339196
  • RO Brady : Emerging strategies for the treatment of hereditary metabolic storage disorders. In: Rejuvenation Res 9, 2006, pp. 237-244. PMID 16706651
  • RH Lachmann: Miglustat: substrate reduction therapy for glycosphingolipid lysosomal storage disorders. In: Drugs Today 42, 2006, pp. 29-38. PMID 16511609
  • TM Cox: Substrate reduction therapy for lysosomal storage diseases. In: Acta Pediatr Suppl 94, 2005, pp. 69-75. PMID 15895716
  • RH Lachmann and FM Platt: Substrate reduction therapy for glycosphingolipid storage disorders. In: Expert Opin Investig Drugs 10, 2001, pp. 455-466. PMID 11227045
  • GM Pastores and NLBarnett: Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. In: Expert Opin Investig Drugs 12, 2003, pp. 273-281. PMID 12556220
  • C. Moyses: Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. In: Philos Trans R Soc Lond B Biol Sci 358, 2003, pp. 955-960. PMID 12803929
  • FM Platt et al: Substrate reduction therapy in mouse models of the glycosphingolipidoses. In: Philos Trans R Soc Lond B Biol Sci 358, 2003, pp. 947-954. PMID 12803928

Special technical articles

  • JM Aerts et al: Substrate reduction therapy of glycosphingolipid storage disorders. In: J Inherit Metab Dis 29, 2006, pp. 449-456. PMID 16763917
  • J. Cox-Brinkman et al: Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III. In: J Inherit Metab Dis 31, 2008, pp. 745-752. PMID 18850301
  • A. Metha: Clinical experience with substrate reduction therapy. In: Eur J Intern Med 17, 2006, pp. 13-15. PMID 17011470
  • B. Bembi et al .: Substrate reduction therapy in the infantile form of Tay-Sachs disease. In: Neurology 66, 2006, pp. 278-280. PMID 16434676
  • A. Andersson et al .: Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. In: Neurobiol Dis 16, 2004, pp. 506-515. PMID 15262262