UCF Researcher: Targeting Mutant Gene May Prevent Huntington’s Symptoms

Released on 10.30.2018

At 27, Danny Miller expected himself to be his company’s “young gun” diesel mechanic. But then he began noticing involuntary muscle movements in his face, hands and feet. He felt weak. His memory was fading.

Danny and Katie Miller. Danny was recently diagnosed with Huntington's disease.

Danny Miller and his wife, Katie, at a Huntington’s Disease Society of America (HDSA) event. Danny was recently diagnosed with Huntington’s.

Doctors gave him a heartbreaking diagnosis: Huntington’s disease, an incurable neurodegenerative disease that causes severe mood changes, cognitive decline and early death.

Scientists describe Huntington’s as having Alzheimer’s disease, schizophrenia and ALS (Lou Gehrig’s disease) all at the same time. They know that a mutant gene causes the disease by stimulating production of an abnormal version of a protein called huntingtin. The protein’s exact purpose in the body remains unclear, but it appears to play a critical role in the function of nerve cells, especially in the brain. So abnormal huntingtin proteins are most harmful to brain nerve cells.

Now a UCF College of Medicine researcher has synthesized pieces of DNA to stop production of mutant huntingtin while leaving normal huntingtin proteins intact. Dr. Amber Southwell’s results, published this month in Science Translational Medicine, showed that after suppressing the mutant protein in mice, damage to their brain function not only ceased, but in some cases was completely reversed.

“For the first time, we showed that by getting rid of this mutant huntingtin protein, psychiatric and mood changes could come back to normal, and this could be done with a potential therapeutic,” Dr. Southwell said. “So we’re pretty excited about it.”

“People are always going to continue to have the mutation. But if we can stop them from ever getting sick, that’s going to be good enough – that would be the end goal. We’re a long way from that, but that’s what we’re working towards.”

About 30,000 Americans have Huntington’s disease and typically live about 15 to 20 years after diagnosis. Carriers have a 50 percent chance of passing Huntington’s on to their children. Miller said he wasn’t surprised by his diagnosis – his father, sister, grandmother and at least three other relatives have Huntington’s or have died from it.

Dr. Amber Southwell

Dr. Amber Southwell

The disease causes severe physical and emotional damage. “You lose your body, your mind, yourself, your personality – everything changes,” Dr. Southwell said. “People are writhing – they can’t sit still. They can’t recognize their relatives and they’re having these psychotic breaks. It’s incredibly devastating.”

Earlier studies have focused on trying to alleviate the motor problems associated with Huntington’s – such as the involuntary dance-like muscle movements called chorea. But few studies have looked at preventing the cognitive and psychiatric aspects, Dr. Southwell said. “If you talk to HD patients and families, these are the things that have the biggest negative impact on their quality of life,” she explained.

Dr. Southwell worked with Ionis Pharmaceuticals to develop modified pieces of DNA called antisense oligonucleotides (ASOs). Once injected into the cerebrospinal fluid — the fluid that bathes the brain — the ASOs keep cells from producing mutant huntingtin.

After being injected with ASOs, mice with cognitive and psychiatric abnormalities similar to those in human Huntington’s patients became less depressed and anxious, with restored learning abilities and no observable side effects, Dr. Southwell said. With the most potent ASO compound, benefits were seen more than 10 months after a single injection.

More testing is needed to better assess how well this could work in humans, but Dr. Southwell and patients like Miller are hopeful.

“It gives us hope to know that we have the advantage of someone fighting for us. We just can’t wait to see how her research continues to unfold,” Miller said.

Since the disease progresses in stages, Miller is left with the gnawing uncertainty of what happens next. He and his wife have decided against having kids, worried not only about passing the disease along to their children, but also about how watching their father “deteriorate” would harm their offspring.

“Probably not knowing exactly when it’s going to start kicking your life in the chest is the hardest part about having it,” he said. “How long is it going to take before you eventually are just helpless?”

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