Gene Therapies for Polyglutamine Diseases

Abstract

Polyglutamine diseases are hereditary degenerative disorders of the nervous system that have remained, to this date, untreatable. Promisingly, investigation into their molecular etiology and the development of increasingly perfected tools have contributed to the design of novel strategies with therapeutic potential. Encouraging studies have explored gene therapy as a means to counteract cell demise and loss in this context. The current chapter addresses the two main focuses of research in the area: the characteristics of the systems used to deliver nucleic acids to cells and the molecular and cellular actions of the therapeutic agents. Vectors used in gene therapy have to satisfyingly reach the tissues and cell types of interest, while eliciting the lowest toxicity possible. Both viral and non-viral systems have been developed for the delivery of nucleic acids to the central nervous system, each with its respective advantages and shortcomings. Since each polyglutamine disease is caused by mutation of a single gene, many gene therapy strategies have tried to halt degeneration by silencing the corresponding protein products, usually recurring to RNA interference. The potential of small interfering RNAs, short hairpin RNAs and microRNAs has been investigated. Overexpression of protective genes has also been evaluated as a means of decreasing mutant protein toxicity and operate beneficial alterations. Recent gene editing tools promise yet other ways of interfering with the disease-causing genes, at the most upstream points possible. Results obtained in both cell and animal models encourage further delving into this type of therapeutic strategies and support the future use of gene therapy in the treatment of polyglutamine diseases.

Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

“…Silencing strategies will benefit from the development of improved RNAi tools; encouraging results have recently been obtained with microRNAs and ASOs (Matos et al . ). Gene therapy strategies will take advantage of delivery vectors with enhanced properties, be it a decreased immunogenicity and toxicity, or improved neuronal selectivity.…”

“…Promising cell and gene‐based approaches for MJD/SCA3 and the other polyQ diseases have emerged from among these strategies (Matos et al . ; Mendonça et al . ).…”

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

“…These abnormal polyQ repeats are the hallmark of incurable, hereditary, and degenerative disorders called polyQ diseases, which include spinal and bulbar muscular atrophy (35 - 38 CAG repeat size), dentatorubropallidoluysian atrophy (49 - 88 CAG repeat size), and various spinocerebellar ataxias (SCA1, 39 - 82 CAG repeat; SCA2, 34 - 64 CAG repeat; SCA3, 60 - 84 CAG repeat; SCA7, CAG repeat 34 - 306) [26,27,28]. Unaffected people have a range between 6 - 35 CAG repeats, with 99% of such individuals having <30 repeats; however, those with HD have 36 - 121 CAG repeats [29,30,31].…”

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

“…Still, since the genetic defects differ from disorder to disorder, the strategy will require adaptations for each disease. As this subject is not the main focus of this review, we will not discuss it in detail, but this subject is reviewed in Matos et al ( 2018 ).…”