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.
CRISPR-Cas9 gene editing alleviates Huntington’s in mouse model
— Shi-Hua and Xiao-Jiang Li. This project is progressing, with funding from NCATS and a pig-oriented collaboration with partners in China.
Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)
— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.
Pilot study shows direct amygdala stimulation can enhance human memory
— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.
Immune responses of five returning travelers infected by Zika virus
— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.
Frog slime kills flu virus
— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.
Enhancing the brain’s own clean-up crews could be a strategy for handling the toxic proteins driving several neurodegenerative diseases, new research suggests.
Astrocytes, an abundant supportive cell type in the brain, are better than neurons at disposing of mutant huntingtin, the toxic protein that drives Huntington’s disease pathology, Xiao-Jiang Li and colleagues report in this week’s PNAS.
One reason why astrocytes are better at toxic protein defense than neurons is: they have less of an inhibitory protein called HspBP1. The scientists show that using CRISPR/Cas9 to “knock down” HspBP1 can help neurons get rid of mutant huntingtin and reduce early pathological signs.
Transgenic Huntington’s disease monkeys display a full spectrum of symptoms resembling the human disease, ranging from motor problems and neurodegeneration to emotional dysregulation and immune system changes, scientists at Yerkes National Primate Research Center, Emory University report.
The results, published online in the journal Brain, Behavior and Immunity, strengthen the case that transgenic Huntington’s disease monkeys could be used to evaluate emerging treatments (such as this) before launching human clinical trials.
“Identifying emotional and immune symptoms in the HD monkeys, along with previous studies demonstrating their cognitive deficits and fine motor problems, suggest the HD monkey model embodies the full array of symptoms similar to human patients with the disease,” says Yerkes research associate Jessica Raper, PhD, lead author of the paper. Read more
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.
Those of us who are old enough to remember vinyl records will recall how a scratch can cause the same sounds to repeat many times. A similar type of genetic glitch causes neurodegenerative diseases such as Huntingtonâ€™s and several forms of spinocerebellar ataxia.
Huntingtonâ€™s and the spinocerebellar ataxias are known as â€œpolyglutamineâ€ diseases. In each, the affected gene has a stretch where the same three DNA letters are repeated several times — more than usual. As a result, the protein encoded by the affected gene has a patch, where only the building block glutamine can be found, disrupting that proteinâ€™s usual functions in the body.
Geneticist Xiao-Jiang Li and colleagues recently published a paper in Cell Reports that may explain why more aggressive juvenile-onset forms of polyglutamine diseases have different symptoms and pathology. Read more
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