The following is a brief survey of HD-related research published during January-March 2020:
Gene therapy refers to the delivery of genetic material to cells in order to treat disease and is an area of active HD research.
In a February study published in Nature Communications, Wu and colleagues from Pennsylvania State University investigated the use of gene therapy to convert a type of glial cell called astrocytes into neurons in a mice model of HD.1 Mice treated with this novel therapy had a significantly longer life span and improved motor functions. These results indicate that gene therapy conversion of glia to neurons could be a feasible way to treat HD.
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. However, a major challenge for ASOs as a viable treatment is the difficulties in effective delivery to the brain.
In a January study published in Angewandte Chemie, a group of Japanese researchers investigated a method of ASO delivery to the brain that is less invasive than current methods.2 Their method involves the passage of ASOs across the blood-brain barrier, a very difficult-to- cross barrier between circulating blood and the brain, using careful glycemic control. Using glucose-coated polymeric nanocarriers, the researchers demonstrated efficient accumulation in brain tissue after intravenous injection and significant inhibition of non-coding RNA in mice. Their results show a novel method of ASO delivery to the brain in a noninvasive manner.
Autophagy refers to a cellular process that works to maintain homeostasis by eliminating unwanted and damaged molecules such as proteins. Researchers have been interested in utilizing this natural process in order to clear aggregates of misfolded proteins common in many neurodegenerative diseases. In the case of Huntington’s disease, many different genetic and pharmacological mechanisms have been used by scientists to induce autophagy and clear harmful aggregates of huntingtin protein.3
In a January report published in Cells, a group of Italian scientists mainly from the University of Milan demonstrated a new way to induce autophagy and clear aggregates of huntingtin.4 Their study showed that regulation of an enzyme called glutamine synthetase 1 (GS1) is able to induce autophagy in a fruit fly model of Huntington’s disease and improve neuronal survival. These findings open up the opportunity for the development of new therapeutics for HD targeting GS1 in future research.
Advances in Understanding HD
Aberrant neuronal development refers to abnormalities in brain cell development and has been implicated in many neurological disorders such as Huntington’s disease.
A March report published in Stem Cell Reports by Smith-Geater and colleagues investigated aberrant development in adult-onset HD.5 Using induced pluripotent stem cells (iPSCs) from HD patients and controls, the researchers identified a mechanism that promotes aberrant neurodevelopment as well as preliminary evidence that specific components of a particular signaling pathway could be a counteractive therapeutic target.
In a January report, a group of scientists from the University of Southern California investigated the effects of treadmill exercise on a mouse model of HD.6 They found that the treadmill exercise resulted in increases in nitric oxide levels as well as improved mitochondrial function. These changes were also associated with improved motor performance. Their findings suggest that in a mouse model of HD, exercise could have a beneficial effect on motor behavior by counteracting deficits in mitochondrial function.
HD and Cardiac Arrhythmias
In recent years, there has been increasing evidence that HD patients could be at an increased risk for cardiac arrhythmias.
In a February study published in Human Molecular Genetics, Zhu and colleagues aimed to investigate this phenomenon in a mouse model of HD.7 Their findings were consistent with prior knowledge, indicating that mutant Huntintin protein (mHTT) can cause problems in cardiac conduction systems, increasing susceptibility to arrhythmias and sudden cardiac death. As a result, the authors suggest that it is beneficial to monitor heart rhythm in HD patients, even when there are no prior signs of heart disease.
The loss of grey matter in a brain region called the hypothalamus has been well-documented in HD, and is believed to contribute to circadian rhythm and habitual sleep disturbances.
In a January study published in the Journal of Neurological Sciences, a group of Australian and British scientists investigated the impact of multidisciplinary rehabilitation therapy on hypothalamic grey matter loss and circadian rhythm and habitual sleep disturbances in a group of individuals with preclinical HD.8 The nine month-long study found that a specialized rehabilitation therapy designed by a team of exercise scientists, cognitive training, sleep, and circadian rhythm specialists, neuroscientists, and a neuropsychiatrist was able to reduce hypothalamic grey matter volume loss. However, the scientists did not observe any significant changes in sleep disturbances.
- Wu, Z., et al., “Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease”. Nature Communications.
- Hyun Su Min et al., “Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier”. Angewandte Chemie.
- Boland, B. et al., “Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing”. Nature Reviews Drug Discovery.
- Vernizzi, L. et al., “Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease”. Cells.
- Smith-Geater, C. et al., “Aberrant Development Corrected in Adult-Onset Huntington’s Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation”. Stem Cell Reports.
- Caldwell, C. et al., “Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington’s disease”. Chemico-Biological Interactions.
- Zhu, Y. et al., “Progressive cardiac arrhythmias and ECG abnormalities in the Huntington’s disease BACHD mouse model”. Human Molecular Genetics.
- Bartlett, D. et al., “Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington’s disease: A nine-month pilot study”. Journal of the Neurological Sciences.