Neue Therapien der spinalen Muskelatrophie

Zusammenfassung

Die 5q-assoziierte spinale Muskelatrophie (5q-SMA) ist eine progressive autosomal rezessive Motoneuronerkrankung mit einer Inzidenz von 1 in 10 000 Geburten. Die 5q-SMA ist durch den Verlust des Survival Motor Neuron 1 Gens (SMN1) verursacht. Sie stellt die häufigste neurodegenerative Erkrankung im Kindesalter dar. 126 Jahre nach der Erstbeschreibung durch Hofmann kam es 2017 zur Erstzulassung einer spezifischen Therapie der SMA in Deutschland. Durch eine Erhöhung des Anteils an funktionsfähigem SMN-Protein, die entweder durch Einschluss von Exon 7 in SNM2-Transkripte, Erhöhung der SMN2-Genexpression oder durch direkten Genersatz von SMN1 erzielt werden kann, ist eine spezifische Therapie nun möglich geworden. Zahlreiche Fragen – was ist der Zeitpunkt für eine optimale therapeutische Intervention, welche therapeutische Maßnahme ist die geeignetste, was sind mögliche Wechselwirkungen gentherapeutischer Maßnahmen – bleiben derzeit noch ungeklärt. Die Kenntnis der klinischen Symptome der SMA und das Wissen um eine spezifische Therapie werden diese bislang als unbehandelbar geltende Erkrankung neu in den medizinischen Fokus bringen, sodass ein früher, nach Möglichkeit präsymptomatischer Therapiebeginn das Outcome im Vergleich zu einem späteren Therapiebeginn entscheidend verbessern wird.

Abstract

5q-associated spinal muscular atrophy (5q-SMA) is a progressive autosomal recessive motor neuron disease with an incidence of 1:10 000 in live births. All types of 5q-SMA are caused by the loss of the survival motor neuron 1 gene (SMN1). SMA represents the most frequent neurodegenerative disorder in children. 126 years after the first description of SMA by Hoffmann, SMA became treatable by a licensed drug. Aggregation of the full-length SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein, or replacing the SMN1 gene opened the therapeutic avenues. Although the SMA research field is rapidly growing, there are still several remaining questions: what is the optimal timing for the intervention, particularly at which point is there irreversible pathology that precludes any meaningful therapeutic response? Knowledge and increased awareness of the disease will help narrowing down the diagnostic delay, which will be crucial for the best therapeutic success.

Schlüsselwörter

Antisense-Oligonukleotid-Therapie - spinale Muskelatrophie - Gentherapie

Keywords

antisense oligonucleotide therapy - spinal muscular atrophy - gene therapy

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