Drilling into the data of HD mouse models
About two decades ago, scientists isolated the gene defective in people with Huntington’s disease, and jumpstarted research into this lethal neurodegenerative disorder. How far the field has progressed since then is a glass half-full, glass half-empty kind of question.
On the one hand, there are drugs in Phase II studies that might help alleviate the debilitating effects of muscle wasting seen in cancer cachexia, muscular dystrophy and other muscle wasting diseases. The thought is that these novel drugs, which are designed to inhibit the signaling pathway for myostatin, a protein over-expressed in patients who have suffered rapid and severe weight loss, might also be useful in addressing the severe muscle atrophy seen in patients with HD. There are also many different mouse and rat models that scientists can use to study the symptoms and pathology of the disease, and to test therapeutic compounds.
Yet the search for effective therapeutics that might slow or prevent this rare inherited disease has been frustrating and disappointing. The one approved drug is Tetrabenazine, which has a moderate, short-lived effect on the writhing, involuntary movements known as chorea, and provokes unpleasant side effects. Many of the other drugs have simply died on the vine. Professor Gillian Bates, a Huntington’s disease researcher who heads the Division of Genetics and Molecular Medicine at King’s College in London has worked on more than 40 different drugs. She says the major challenge continues to be validating the novel therapeutic targets in animal models. “At least this gives us confidence we are not working within the noise,” Bates said during a Monday morning symposium at the Society for Neuroscience meeting.
One approach scientists are using to try and bridge the translational gap between mice and men, and bring the HD models into greater focus, is with neuroimaging. For over a year now, Charles River’s Finland site, which focuses on diseases of the central nervous system (CNS), has been using a kind of motion-capture computer-generated imagery to detect subtle phenotypic changes with earlier and more sensitive detection compared to traditional movement analysis. The earliest studies of fine motor kinematic analysis, which Eureka blogged about here and here, began in rodents that model certain aspects of HD. At the SfN meeting, Taneli Heikkinen, a CR scientist in Chronic Neurology, presented a new round of data on Monday that showed highly significant changes much earlier in the two mouse models. “In our first study we characterized mice at the symptomatic stage,” said Heikkinen. “This time we fine-tuned the algorithms and also went on to see if these changes could be seen even sooner.”
In the R6/2 mouse model—transgenic model with early and rapid disease progression—the kinematic analysis found subtle gait and fine motor deficits as early as four weeks of age, when the mice are still largely asymptomatic for HD. The characteristic changes included for instance disturbed cadence, increased joint angle ranges and increased stance time. Changes in heterozygote zQ175 knock-in (KI) mice were observed from six months of age and from three months of age in homozygote zQ175 knock-in (KI) mice.
Heikkinen said the tool offers more sensitivity than conventional rodent motor tests in detecting deficits, and could be useful in validating drugs that target the disease at the earliest phases, when the HD symptoms are not as pronounced.
The Finland site has also used radiotelemetry, a common tool ubiquitous on cardiac care units, to collect data on three biological parameters off-kilter in HD patients and, as it turns out, HD mice. Driven by one’s biological clock, these physical, mental and behavioral changes otherwise known as circadian rhythms follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. It’s not entirely clear why these rhythms are out of step in HD patients, but the traits have been replicated in animal models, including the R6/2 model, which also is prone to hypothermia, particularly at night, as the disease progresses.
To conduct the Charles River study, scientists first implanted miniaturized telemetric transmitters in the abdomens of R6/2 and zQ175 KI mice, and then housed the animals in home cages that were kept over receiver platforms so the scientists could record data from the implanted transmitters.
Juho Oksman, a CR scientist in Chronic Neurology who presented findings of his team’s work at SfN, said the study set out to characterize the circadian and cardiac abnormalities over a three-month period from 7-9 months in the zQ175 KI mice and at weeks 9 and 15 in the R6/2 mice. The earlier times in the R6/2 mice accounted for the fact that HD progresses earlier in this model.
Oksman said the found that both HD models were hypoactive and had lower body temperatures during the nocturnal phase compared to wild-type mice. Between nine and 15 weeks of age, the heart rate of the R6/2 mouse also became more pronounced, though the heart rate of the zQ175 KI mouse was stable. Oksman said the study shows the utility of using telemetry to conduct real-time remote monitoring of biological parameters in freely-moving animals.