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Lysosomale Speicherkrankheiten: Therapeutische Optionen

Lysosomal storage diseases: treatment options

Zusammenfassung

Für einige lysosomale Speicherkrankheiten steht eine Enzymersatz-Therapie zur Verfügung oder wird derzeit entwickelt. Um zu erreichen, dass intravenös applizierte Enzyme das Zentralnervensystem erreichen, werden Methoden entwickelt, durch Modifizierung der Enzyme oder durch Anwendung von Nanopartikeln die Bluthirnschranke zu überwinden. Eine andere Therapie-Option besteht in der Anwendung von Substrathemmern, die für den M. Gaucher und den M. Niemann-Pick Typ C eingesetzt werden. Derzeit werden Chaperone für verschiedene lysosomale Speicherkrankheiten entwickelt, die jedoch den Nachteil haben, dass sie nur bei bestimmten Mutationen eingesetzt werden können. „Read-Through“ Substanzen werden lediglich bei Vorliegen einer Nonsense-Mutation wirksam sein können. Auf dem Gebiet der lysosomalen Speicherkrankheiten wird eine Gen-Therapie derzeit nur im Rahmen klinischer Studien durchgeführt. Bevor dieses Behandlungs-Prinzip breite Anwendung finden kann, sollten jedoch noch Fragen zum Beispiel bezüglich der Langzeit-Sicherheit, der möglichen Immun-Reaktion und der Organ-Spezifität des für die Insertion verwendeten Vektors beantwortet werden. Um eine Behandlung einleiten zu können, bevor irreversible Organschäden auftreten, ist in vielen Ländern ein Neugeborenen-Screening für lysosomale Speicherkrankheiten eingeführt worden. Da jedoch damit mehr Mutationsträger diagnostiziert wurden als auf Grund epidemiologischer Untersuchungen zu erwarten war, muß angenommen werden, dass auch sehr leicht betroffene Patienten damit erfaßt werden. Eine sichere Aussage über den zu erwartenden Schweregrad kann jedoch auch durch eine Gen-Analyse nicht gemacht werden, so dass eine Therapie-Entscheidung im Einzelfall eventuell sehr schwierig ist. Für dieses Dilemma ist bisher noch keine Lösung gefunden worden.

Abstract

For some lysosomal storage disorders enzyme replacement therapy is available or is under development. In order to ensure that intravenously applied enzymes reach the central nervous system, methods to overcome the blood-brain barrier by modification of the enzymes or by the use of nanoparticles are being developed. Substrate deprivation represents another therapeutic option that is available for Gaucher disease and Niemann-Pick disease type C. One disadvantage of chaperones is the fact that they are effective only for patients with specific mutations. “Read-through” drugs will be useful only for patients who bear a nonsense-mutation. Presently gene therapy is being used as a therapeutic intervention for lysosomal storage disorders only in clinical trials. Before this treatment can be declared a routine therapeutic procedure, many questions have to be answered regarding, for example, long-term safety, immune reactions and organ specifity of the vector used for insertion of the gene. In many countries, newborn screening for lysosomal storage disorders has been introduced to allow timely initiation of treatment before any clinical manifestation occurs. However, since by screening many more cases have been found than was expected from epidemiological studies, it must be assumed that also such patients are being detected who are very mildly affected and probably do not need any therapy. As the severity of a disease cannot be predicted precisely by mutation analysis, a decision as to when to start treatment may be difficult in individual cases. No solution has been found for this dilemma to date.

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Correspondence to Michael Beck.

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Michael Beck hat Honorare, Reiseunterstützung und wissenschaftliche Förderung erhalten von Shire, Genzyme, Biomarin und Actelion.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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Beck, M. Lysosomale Speicherkrankheiten: Therapeutische Optionen. medgen 27, 276–281 (2015). https://doi.org/10.1007/s11825-015-0057-z

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Schlüsselwörter

  • Lysosomale Speicherkrankheit
  • Enzymersatz-Therapie
  • Substrathemmer
  • Chaperon
  • Gen-Therapie

Keywords

  • Lysosomal storage diseases
  • Enzyme replacement therapy
  • Substrate deprivation
  • Chaperone
  • Gene therapy