A lot is happening in the Huntington’s disease (HD) field right now. Emory research reports on a pig HD model and on CRISPR/Cas9 gene editing are just part of the wave.
Let’s step back and review the technologies now available to treat this neurodegenerative disease, caused by a gene producing a toxic protein. Antisense approaches, under development for decades and now in clinical trials, shut off the problematic gene. However, this type of treatment would need to be regularly delivered to nervous system tissues. Gene editing — not in the clinic yet — could actually remove the gene from somatic cells in affected individuals.
Emory researchers developed the pig HD model in collaboration with colleagues in Guangzhou, and anticipate it will be a practical way to test treatments such as gene editing. In comparison with mice, delivery to affected nervous system tissues can be better tested in pigs, because their size is closer to that of humans. The pig model of HD, published yesterday in Cell, also more closely matches the symptoms of the human disease. This research was covered by Chinese media organizations.
Adult mice don’t need the gene that, when mutated in humans, causes the inherited neurodegenerative disorder Huntington’s disease.Â The finding suggests that treatment strategies for Huntington’s that aim to shut off the huntingtin gene in adults — now in early clinical stages — could be safe.
The results were publishedÂ Monday, March 7 inÂ PNAS.
How HD gene silencing is supposed to work. The Emory study didn’t test this approach directly, but the Emory studyÂ has implications for what types of side effects HD gene silencingÂ may have in humans. Image from HDBuzz.net via Creative Commons.
Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline. A juvenile form of Huntington’s disease also can appear during the teenage years.
Researchers led by Xiao-Jiang Li, MD, PhD and Shihua Li, MD, at Emory University School of Medicine, used genetically engineered mice in which the huntingtin gene can be deleted, triggered only when the mice are given the drug tamoxifen. Note: these mice don’t produce toxic mutant huntingtin protein.
When the huntingtin gene is deleted at an age older than four months, these mice appeared to stay healthy, despite having lost their huntingtin genes in cells all over their bodies. They maintained their body weight and could complete tests of movement and grip strength as well as control mice.Â In contrast with adults, engineered mice younger than four months old whose huntingtin gene was deleted developed lethal pancreatitis.
The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.
Researchers at Emory University School of Medicine led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhDÂ have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.
The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Ray Ban outlet Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.
The results were published recently in the journalÂ Neuron. Read more