New frontiers in the treatment of Huntington's disease

Novel disease-modifying therapies are under investigation in HD

HD is caused by a cytosine–adenine–guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT) resulting in the production of a toxic mutant HTT (mHTT) protein.4-6,33 mHTT causes progressive neuronal degeneration, ultimately leading to neuronal cell death.5,33,34 Levels of mHTT in cerebrospinal fluid correlate with disease stage, symptom severity and markers of neuronal damage in people with HD.34

Novel disease-modifying therapies are being investigated in both pre-clinical and clinical studies, exploring different approaches to slow or stop progression of this debilitating disease.27,37-39

Click here to see the ongoing trials in HD

Disease-modifying therapies under investigation include antisense oligonucleotides (ASOs), gene therapies and small molecule splice modifiers:

1. Antisense oligonucleotides (ASOs)

Antisense oligonucleotides (ASOs), administered intrathecally, have the potential to change the therapeutic landscape for many neurological conditions including HD.37

ASOs are short, synthetic strands of nucleic acids, typically between 16–20 nucleotides in length, that bind to target pre-mRNA or mRNA and reduce, modify or restore protein expression.37,38 There are several distinct mechanisms of action of ASOs depending on their chemistry, binding sequence and target.37. In current HD research, once bound to the RNA, ASOs form an RNA‑DNA hybrid, and the target mRNA is degraded, preventing translation into protein.37-39

Allele-specific (targeting only the mutant allele) and non-allele specific (targeting both wild-type and mutant alleles) approaches are under investigation for lowering HTT.38,40

ASO target degradation MoA

2. Gene therapy

According to the FDA, “Human gene therapy aims to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use”.41 There are several approaches; those currently under investigation for HD include one‑off intrastriatal administration of genes encoding microRNA (miRNA) or zinc finger proteins (ZFPs).40,42,43 miRNAs are small non‑coding RNAs that play important roles in regulating gene expression.44 ZFPs are proteins that can bind DNA and play a role in a range of cellular processes, including development, differentiation and neurodegeneration.43,45

Genetic material-encoding miRNA or ZFPs are delivered using viral vectors,43 which lack viral DNA and are designed to cross the cell membrane to deliver the novel genetic material.46

The miRNA approach suppresses translation through RNA interference (RNAi): binding of miRNA to HTT mRNA transcripts induces their degradation, thereby preventing translation into protein.40

RNA interference

The ZFP approach suppresses transcription of the mHTT gene. ZFPs for HD have been developed to bind selectively to the CAG repeat expansion, and therefore may preferentially suppress transcription of the mHTT allele and reduce production of the mHTT protein.43

Zinc finger proteins

3. Small molecule splice modifiers

Pre-mRNAs are new, immature strands of messenger RNA (mRNA) following transcription that contain both introns (non-coding sections) and exons (coding sections).47 RNA splicing is a form of RNA processing in which the newly made pre-mRNA transcript is transformed into a mature mRNA. During splicing, introns are removed and exons are joined together.48 Small molecule splice modifiers can be used to inhibit protein production by altering the splicing of pre-mRNA.40,49,50 These orally bioavailable small molecules can penetrate the blood‑brain-barrier and are under investigation in HD to lower levels of mHTT.40,51

To see the latest news in HD research, go to HDBuzz

You can explore ongoing clinical trials in HD and find studies that are actively recruiting participants at HD Trial Finder.

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