Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.

Die Huntington-Krankheit (HK) ist die häufigste monogenetische neurodegenerative Erkrankung und kann bereits im präklinischen Stadium zweifelsfrei diagnostiziert werden, zumindest in allen Fällen, bei denen die CAG-Expansionsmutation im Huntingtin-Gen (HTT) im Bereich der vollen Penetranz liegt. Wichtige Voraussetzungen für eine früh im Krankheitsprozess einsetzende und deshalb den weiteren Verlauf der Krankheit in klinisch relevanter Weise modifizierende Therapie sind damit gegeben und machen die HK zu einer Modellerkrankung für neuroprotektive Behandlungsansätze. In der Vergangenheit lag der Schwerpunkt auf dem Ausgleich vermuteter Neurotransmitterdefizite (GABA) analog zur Parkinson-Erkrankung und auf klassischen neuroprotektiven Strategien zur Beeinflussung hypothetischer gemeinsamer Endstrecken neurodegenerativer Erkrankungen (z. B. Exzitotoxizität, mitochondriale Dysfunktion, oxidativer Stress etc.). Mit der Entdeckung der krankheitsverursachenden HTT-Mutation im Jahr 1993 fokussierte sich die Therapieforschung zunehmend darauf, soweit proximal wie möglich in die pathophysiologische Ereigniskette einzugreifen. Ein wichtiger Ansatzpunkt ist hier die HTT-mRNA mit dem Ziel, die Nachproduktion mutierter Huntingtin-Genprodukte zu senken und damit den Körper von deren schädigenden Auswirkungen zu entlasten; zu diesem Zweck sind verschiedene Behandlungsmodalitäten (einzelsträngige DNA und RNA, divalente RNA und Zinkfinger-Repressorkomplexe, oral verfügbare Spleißmodulatoren) entwickelt worden, die sich in der klinischen Prüfung (Phase I–III) oder in späten Stadien der präklinischen Entwicklung befinden. Zudem zeichnet sich ab, dass es möglich sein könnte, die Länge der somatisch instabilen, d. h. über die Lebenszeit v. a. im Hirngewebe zunehmende CAG-Mutation selbst zu beeinflussen und die Progression der HK hierdurch zu bremsen.

Huntington Zentrum Süd kbo Isar Amper Klinikum Taufkirchen Deutschland

Klinik für Neurologie und Zentrum für klinische Neurowissenschaften 1 Medizinische Fakultät Karlsuniversität Prag Tschechien

Klinik für Neurologie Universität Ulm Oberer Eselsberg 45 1 89081 Ulm Deutschland

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