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.

• Klíčová slova
• Antisense oligonucleotide, Disease modification, Gene therapy, HTT mRNA, Neuroprotection,
• MeSH
• antisense oligonukleotidy MeSH
• Huntingtonova nemoc * diagnóza   farmakoterapie   genetika   MeSH
• lidé MeSH
• mozek MeSH
• mutace genetika   MeSH
• neurodegenerativní nemoci * MeSH
• protein huntingtin genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antisense oligonukleotidy MeSH
• protein huntingtin MeSH

In Germany at least 8000 and probably up to ca. 14,000 people currently suffer from clinically manifest Huntington's disease (HD). In addition, an estimated 24,000 Germans carry the HD mutation in the huntingtin (HTT) gene and will develop HD during their lifetime. Although HD is a rare neurodegenerative disease, it is currently in the focus of general medical interest: clinical trials have begun that provide a rational basis for hope to slow down the so far relentless progression of the disease, ultimately resulting in patients becoming entirely dependent on nursing care. If treatment is started early enough it may be possible to mitigate the clinical manifestation of HD. These innovative therapeutic approaches aim at inhibiting the de novo production of mutant HTT gene products. A first clinical drug trial to demonstrate the efficacy (phase III) of intrathecal antisense oligonucleotides (ASO, active substance RG6042) was started in 2019. Additional clinical studies on alternative treatment approaches with allele-selective ASOs as well as gene therapeutic approaches using RNA molecules and zinc finger repressor complexes are imminent. This article gives an overview of the current gene-selective therapeutic approaches in HD under discussion.

• Klíčová slova
• Adeno-associated viruses, Antisense oligonucleotide, Gene therapy, Huntingtin, Zinc finger repressor complexes,
• MeSH
• antisense oligonukleotidy terapeutické užití   MeSH
• genetická terapie * trendy   MeSH
• Huntingtonova nemoc * terapie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• protein huntingtin genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Geografické názvy
• Německo MeSH
• Názvy látek
• antisense oligonukleotidy MeSH
• protein huntingtin MeSH

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Previously, we showed strong huntingtin reduction and prevention of neuronal dysfunction in HD rodents using an engineered microRNA targeting human huntingtin, delivered via adeno-associated virus (AAV) serotype 5 vector with a transgene encoding an engineered miRNA against HTT mRNA (AAV5-miHTT). One of the challenges of rodents as a model of neurodegenerative diseases is their relatively small brain, making successful translation to the HD patient difficult. This is particularly relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure. Here, we aimed to demonstrate the translation of huntingtin-lowering gene therapy to a large-animal brain. We investigated the feasibility, efficacy, and tolerability of one-time intracranial administration of AAV5-miHTT in the transgenic HD (tgHD) minipig model. We detected widespread dose-dependent distribution of AAV5-miHTT throughout the tgHD minipig brain that correlated with the engineered microRNA expression. Both human mutant huntingtin mRNA and protein were significantly reduced in all brain regions transduced by AAV5-miHTT. The combination of widespread vector distribution and extensive huntingtin lowering observed with AAV5-miHTT supports the translation of a huntingtin-lowering gene therapy for HD from preclinical studies into the clinic.

• Klíčová slova
• AAV, Huntington disease, gene silencing, microRNA, transgenic minipig,
• MeSH
• Dependovirus genetika   MeSH
• expanze trinukleotidových repetic genetika   MeSH
• genetická terapie metody   MeSH
• genetické vektory genetika   MeSH
• geneticky modifikovaná zvířata MeSH
• Huntingtonova nemoc genetika   metabolismus   terapie   MeSH
• lidé MeSH
• mikro RNA genetika   metabolismus   MeSH
• miniaturní prasata MeSH
• modely nemocí na zvířatech MeSH
• prasata MeSH
• protein huntingtin genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mikro RNA MeSH
• protein huntingtin MeSH

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CβA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA.

• Klíčová slova
• AAV, Huntington's disease, RNAi, large animal models,
• MeSH
• Dependovirus genetika   MeSH
• elektrolyty metabolismus   MeSH
• genetické vektory metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• genom virový MeSH
• Huntingtonova nemoc genetika   patologie   MeSH
• imunoanalýza MeSH
• injekce MeSH
• játra patofyziologie   MeSH
• ledviny patofyziologie   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikro RNA genetika   metabolismus   MeSH
• mikroglie metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mutantní proteiny metabolismus   MeSH
• neostriatum metabolismus   MeSH
• neurony metabolismus   MeSH
• ovce MeSH
• protein huntingtin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• elektrolyty MeSH
• HTT protein, human MeSH Prohlížeč
• messenger RNA MeSH
• mikro RNA MeSH
• mutantní proteiny MeSH
• protein huntingtin MeSH