Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

Abstract

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

“…However, data awareness in terms of pharmacological HD drug targets and potential agents is also crucial for novel drug discovery, design, and development. In fact, the target landscape with respect to HD is rich and diverse, which leaves much space for rational drug design approaches [ 2 , 14 , 15 , 17 , 20 , 21 , 22 , 27 , 35 , 79 ]. Many compounds with affinities to one or several of these targets have also been identified.…”

“…(i) Neurotransmitter systems, which are addressed by many off-label-use anticholinergics, antidepressants, and antipsychotics such as risperidone [ 14 , 15 , 17 , 19 , 35 , 86 ] mirtazapine [ 2 , 14 , 17 , 19 ], and memantine [ 14 , 19 , 20 , 79 , 86 , 87 , 88 ]. The respective targets include DRs, 5HTRs, or NMDARs, but also choline esterases/receptors (ChEs/ChRs) [ 14 , 15 , 17 , 19 , 35 , 79 , 86 , 87 ], adrenoreceptors (αRs) [ 2 ], and γ-amino butyric acid receptors (GABARs) [ 14 , 17 , 79 , 87 , 89 ].…”

“…(ii) Mitochondrial systems, which are addressed by a large number of molecules, including compounds that protect mitochondria and rescue mitochondrial membrane potential [ 56 , 79 , 86 , 90 , 91 , 92 ], promote mitochondrial biogenesis [ 14 , 15 , 20 , 79 ], as well as enhance mitochondrial respiration and function [ 14 , 20 , 79 ]. These observations have been made for several compounds, such as minocycline [ 86 , 90 ], fenofibrate [ 14 , 15 , 20 , 79 ], and triheptanoin [ 14 , 20 , 79 ]. As mitochondrial deterioration is assumed to be a side effect of HD, these and other molecules with similar function will most likely not lead to a curative treatment.…”

“…However, no causative, disease-modifying treatment is to this date available to stop, slow down, or reverse the disease progression or even delay HD onset [ 6 ]. Several promising target structures apart from HTT have been identified to potentially be involved in the HD pathogenesis, including cysteine aspartases (caspases, CASPs) [ 2 , 14 , 15 , 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], heat shock proteins (HSPs) [ 2 , 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], histone deacetylases (HDACs) [ 2 , 14 , 15 , 17 , 20 ], phosphodiesterases (PDEs) [ 14 , 15 , 17 , 31 , 35 , 36 ], or sigma-receptors (σRs) [ 14 , 15 , 35 , 37 ], amongst several others. Many interesting drug candidates were discovered targeting these and other cerebral targets, however, the reason for their positive effect on in vitro or in vivo HD models remains unclear, and the mechanisms of action toward their primary targets still need to be elucidated [ 38 , 39 ].…”

The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives

“…Third, a more personalized approach, depending on the stage of the disease and the abnormally functioning pathways in each individual patient could be more rewarding since the “one size fits all” approach has failed. Specific biomarkers could identify these pathways, which could be normalized by using miRNAs and small interfering RNAs (siRNAs) delivered by exosomes to modulate these pathways [ 265 ].…”