Abstract
Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington’s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.
Highlights
The disease manifests as a movement disorder in about 60% of cases, cognitive deficits dominate the initial clinical picture in 14% and psychiatric abnormalities are the initial presentation in about 20% of cases
Current pharmacotherapy in Huntington’s disease (HD) is limited to symptomatic treatment of movement disorders and psychiatric symptoms
antisense oligonucleotide (ASO)-based therapies have already been approved for several diseases including both aforementioned neuromuscular diseases
Summary
Huntington’s disease (HD) is clinically characterized by a triad of movement disorders, psychiatric symptoms and cognitive deficits. Dystonia and bradykinesia are common as well [1]. They may even be the sole movement abnormality, especially in juvenile HD. The disease manifests as a movement disorder in about 60% of cases, cognitive deficits dominate the initial clinical picture in 14% and psychiatric abnormalities are the initial presentation in about 20% of cases. Psychiatric symptoms include irritability, aggressive behavior and disturbed impulse control or apathy [2]. The diagnosis of clinically manifest HD is currently exclusively based on the presence of motor symptoms [3]. Current pharmacotherapy in HD is limited to symptomatic treatment of movement disorders and psychiatric symptoms. Despite numerous clinical studies on disease-modifying strategies (see e.g., homepage of the Huntington Study Group), far, no therapy exists that is able to slow down, stop or even reverse the course of the disease
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