The following is a brief survey of HD-related research published during April-June 2020:
Antisense oligonucleotides are short strands of DNA that interact with messenger RNA, the precursors of proteins. Researchers have been investigating the use of antisense oligonucleotides (ASOs) to prevent the production of certain maladaptive proteins that cause disease and the technique has shown great promise for HD, which is caused by a mutant HTT protein.
In an April study published in Neurology, Hawellek and colleagues investigated the effects of treatment with an antisense oligonucleotide called RG6042 on patients with early manifest HD.1 They monitored changes in brain activity using a technique called electroencephalography that records electrical activity in the brain. The researchers found that RG6042 treatment caused an increase in brain electrical activity signal power in a frequency range that was depressed in the HD patients. These results indicate that RG6042 may mediate recovery of brain activity in HD patients, but more research as to whether this translates into a therapeutic benefit is needed.
Small Molecule Inhibitors
A June report published in ACS Chemical Neuroscience aimed to investigate the ability of several small molecules to hinder Huntingtin protein aggregation, a major aspect of Huntington’s disease.2 Direct blocking of aggregate formation is an under-investigated approach to therapeutic discovery for HD, making this study particularly exciting. Using a method called fluorescence resonance energy transfer, or FRET, Lo and colleagues engineered two biosensors that could be utilized to monitor aggregation of Huntingtin protein in live cells. They then used high-throughput screening, an automated method of testing of large numbers of potential drugs, in order to discover effective candidates. They found six small molecules that displayed a decreased FRET of the biosensors, indicative of aggregate breakage. Furthermore, these compounds were also found to reduce aggregate-induced cell death in affected cells. While these results are promising, considerable work needs to be done before these small molecules can be recognized as viable therapeutic options for HD.
A major challenge for ASOs as a viable treatment is the difficulties in effective delivery to the brain. As such, determining better methods for drug delivery is an incredibly important area in HD research.
In an April study published in Neurology, Leavitt and colleagues investigated intrathecal drug administration of RG6042, the same experimental ASO for Huntington’s disease investigated by Hawellek and colleagues.3 The group of researchers used two clinical studies to derive insights on best practice for intrathecal drug administration, or injection of therapeutics into the spinal canal, in Huntington’s disease. The researchers reported gaining substantial insights into the real-world considerations of intrathecal administration via lumbar puncture. Their findings are a considerable step towards making intrathecal administration of HD therapeutics more feasible in the clinical setting.
Progressive cognitive disturbances are a defining clinical characteristic of HD. Cognitive training is a promising therapeutic strategy in order to slow cognitive decline. However, its efficacy, specifically for HD patients, is not well understood and current research aims to clarify its impact.
In a June report published in Pilot and Feasibility Studies, Yhnell and colleagues aimed to investigate the feasibility and acceptability of a home-based computerized executive function training program called CogTrainHD.4 The researchers found that many of the participants did not strongly adhere to the intervention, indicating that CogTrainHD is not feasible in its current state. In future studies, the research group aims to rectify the shortcomings of this study.
Another June study published in Pilot and Feasibility Studies looked at the feasibility of mindfulness-based cognitive therapy (MBCT) for people with the HD genetic mutation.5 Specifically, Eccles and colleagues were looking to determine if eligible persons would be willing to participate in a randomized controlled trial to analyze the effect of MBCT on people with the HD mutation, either pre-manifest or in an early disease stage. The group concluded that difficulties in recruiting and relative rarity of HD makes an in-person MBCT randomized controlled trial highly improbable. The researchers are currently looking at online methods of administration in order to make a randomized controlled trial feasible.
- Hawellek, D., et al., “Changes in Brain Activity with Antisense Oligonucleotide RG6042 Treatment in Early Manifest Huntington’s Disease (HD)”. Neurology.
- Lo, C., et al., “Discovery of Small Molecule Inhibitors of Huntingtin Exon 1 Aggregation by FRET-Based High-Throughput Screening in Living Cells”. ACS Publications.
- Leavitt, B., et al., “Intrathecal Drug Delivery of Antisense Oligonucleotides in Huntington’s Disease: Experience of Ionis/Roche RG6042 Development Programme and Best Practice Considerations for Real-World Use”. Neurology.
- Yhnell, E., et al., “A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington’s disease (CogTrainHD)”. Pilot and Feasibility Studies.
- Eccles, F., et al., “A feasibility investigation of mindfulness-based cognitive therapy for people with Huntington’s disease”. Pilot and Feasibility Studies.