Huntingtin Lowering Strategies

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.

STIM2 Mediates Excessive Store-Operated Calcium Entry in Patient-Specific iPSC-Derived Neurons Modeling a Juvenile Form of Huntington's Disease

“…Since HD is a monogenic disease, the only way to totally treat it is to prevent the expression of the mutant huntingtin. One of the rapidly developing therapeutic approaches is using antisense oligonucleotide technology to lower huntingtin levels in HD (Aslesh and Yokota, 2020 ; Marxreiter et al, 2020 ). However, the searching for the small molecules able to supplement and/or enhance action of antisense oligonucleotides remains highly actual.…”

New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

“…How might this new information about DNA repair affect therapeutic efforts for HD and other triplet repeat expansion diseases? A major effort is currently underway to treat HD by lowering the levels of huntingtin protein [108,109] (Fig. 4).…”

“…How might this new information about DNA repair affect therapeutic efforts for HD and other triplet repeat expansion diseases? A major effort is currently underway to treat HD by lowering the levels of huntingtin protein [ 108 , 109 ] ( Figure 4 ). The idea is that less huntingtin—especially less of the mutant version of the protein—will reduce HD symptoms and relieve suffering.…”

“…The idea is that less huntingtin—especially less of the mutant version of the protein—will reduce HD symptoms and relieve suffering. As an example, antisense oligonucleotides (ASOs) have been developed that inhibit translation of huntingtin by targeting its messenger RNA [ 108 , 109 ]. One such ASO was reported in a Phase I/IIa clinical study to be safely tolerated and to reduce huntingtin levels in spinal fluid by up to 40% [ 110 ].…”

Nuclear Envelope and Nuclear Pore Complexes in Neurodegenerative Diseases—New Perspectives for Therapeutic Interventions

“…Nuclear accumulation of Htt is associated with increased phosphorylation of Ser13 and Ser16 [ 81 , 82 ] of the N-terminal of Htt and decreased interaction with the nuclear pore protein Tpr, which is involved in the nuclear export of proteins [ 7 , 81 , 83 ]. Huntingtin-lowering strategies may become promising therapeutic options in the future [ 84 ].…”