Neuron Finding Lifts Hopes for Down Syndrome Drug

from Joan Arehart-Treichel, Psychiatric News:

Discovering a dearth of acetylcholine and norepinephrine in the hippocampus of a mouse model of Down syndrome opens promising therapeutic avenues for people with the disorder.

Down syndrome is usually due to each cell in the human body having three copies, rather than two copies, of chromosome 21. This heartbreaking illness leads not just to a spate of physical abnormalities and cognitive dysfunction, but often to early-onset Alzheimer’s disease.

A pivotal brain region affected by Down syndrome is the hippocampus. Now scientists at Stanford University School of Medicine have made two important findings about what occurs in that region in a mouse model of Down syndrome, which purportedly translates to people with the syndrome.

 

One is a loss of two types of neurotransmitter-producing neurons in the hippocampus—acetylcholine-producing neurons and norepinephrine-producing neurons. The other is that this loss is linked with the overexpression of the amyloid precursor protein gene in the hippo-campus. Mutations in this gene, which is located on chromosome 21, are known to lead to early-onset Alzheimer’s, and it may be that early onset of Alzheimer’s pathology in people with Down syndrome is due in part to overexpression of the amyloid precursor protein gene.

 

These findings have provocative therapeutic implications for people with Down syndrome, the scientists also pointed out online September 27 in Biological Psychiatry. For instance, although the amyloid precursor protein gene should be a primary therapeutic target in Down syndrome, there are no safe and effective medications on the market to reduce the gene’s expression. In contrast, since a paucity of norepinephrine-producing neurons in the hippo-campus also seems to contribute to Down syndrome, medications that enhance norepinephrine levels in the brain and are already on the market to treat attention-deficit/hyperactivity disorder might be of therapeutic benefit to individuals with Down syndrome.

 

Moreover, such medications might also subdue the action of the amyloid precursor protein gene in such individuals, they speculated.

 

“We are indeed working on this group of drugs—drugs that are able to increase norepinephrine levels and that have already been approved by the Food and Drug Administration—in our mouse models,” Ahmad Salehi, M.D., Ph.D., a clinical associate professor of psychiatry at Stanford and the study’s senior investigator, told Psychiatric News. “This strategy could speed up the development of a treatment for cognitive function in Down syndrome enormously.”

 

The scientists’ discovery of a paucity of acetylcholine-producing neurons in the hippocampus of an animal model of Down syndrome holds therapeutic promise, the researchers noted. In fact, other researchers reported eight years ago that the Alzheimer’s drug donepezil, which slows the break down of acetylcholine in the brain, might improve cognitive scores and expressive language in children and adults with Down syndrome.

 

Yet if donepezil improves cognitive function and language in these individuals, is there reason to believe that medications that increase norepinephrine would be superior to donepezil in that regard? Asalehi believes there is. “I think using norepinephrine-ergic drugs would be far superior to cholinergic ones for the following reasons: The norepinephrine system has some regulatory effects on the cholinergic one. It has been shown that lesions in the former lead to increased severity of cholinergic deficits; most adults with Down syndrome will show Alzheimer’s-related pathology, particularly amyloid plaques. There are new studies showing that increasing norepinephrine levels in mouse models of Alzheimer’s significantly reduce amyloid accumulation. These findings suggest that using norepinephrine-ergic drugs might not only restore cognition in kids with Down syndrome, but also reduce Alzheimer’s-related pathology in adults with the syndrome.”

 

“Studies such as this one help to further our overall understanding of central nervous system function and in particular differences seen in individuals with Down syndrome,” Melanie Manning, M.D., director of the Center for Down Syndrome at Stanford’s Lucile Packard Children’s Hospital, told Psychiatric News.

 

“Many of the families of individuals with Down syndrome follow results from research studies such as this one with great interest. They express a desire to learn more about potential clinical applications that lie ahead.”

 

The research was funded by the Mental Illness Research, Education, and Clinical Center Department of Veterans Affairs; Down Syndrome Research and Treatment Foundation; Thrasher Foundation; and Alzheimer’s Association.

 

Ahmad Salehi, M.D., Ph.D.: 

 

An abstract of “Neurobiological Elements of Cognitive Dysfunction in Down Syndrome: Exploring the Role of APP” is posted at <www.biologicalpsychiatryjournal.com/article/S0006-3223(11)00822-5/abstract>.

Drug treatment for people with intellectual disabilities

From the Los Angeles Times:

Slouched sideways at his desk in the front row of class, a sneakered foot jittering distractedly, Chase Brown could be any 14-year-old in academic captivity.

As the discussion turns to the American history of slavery, the teacher draws Chase back from his apparent reverie. A classmate has said that Abraham Lincoln freed the slaves. Does Chase agree or disagree?

Chase locks eyes with his teacher. "I agree," he says emphatically.

It is a moment of triumph for Chase, one of an estimated 90,000 in the U.S. who live with an inherited form of intellectual disability known as fragile X syndrome. Only a year ago, he would have fled the classroom, thrown something at the teacher or stayed mute. Last year, he tested below first-grade level in all academic domains.

Impulsive, distracted and quick to boil over, he seemed incapable of learning.

This year, he can sit in a classroom for half an hour before needing a "sensory break": a walk around the parking lot to clear his overstimulated brain. He is reading at a fourth-grade level, following class discussions, looking teachers squarely in the eyes and answering questions.

On a surprising drug — a workhorse antibiotic used since the 1960s to treat acne, skin infections, strep throat and chlamydia — Chase is learning.

Minocycline, the medication Chase has been taking for almost eight months, is one of several drugs that might correct — even reverse — many of the brain perturbations of fragile X and several other developmental disorders, including autism.

The medications are still far from proven: Large-scale trials may take several years to complete. But if they live up to their promise without dangerous side effects, they could accomplish what no medication has been able to: cure a genetically based intellectual disability.

Last year, Chase was among the first 50 children and adults with fragile X to take the drug as an experimental treatment. Since then, said his mother, Heather Brown, he has changed in ways she hadn't thought possible.

He has developed the ability to chat: share details of his day, make thoughtful observations and inquiries, and respond with apparent understanding, even empathy.

His explosions of kicking, hitting and object hurling, and the terrible remorse that followed, have vanished.

It's not sedation: She saw that before when Chase cycled through a list of powerful antipsychotic medications. He seems instead to be learning new ways to behave.

"It's life-changing, it really is," said Brown, who lives in Mission Viejo with Chase and his stepfather. "I was, like, 'Minocycline? They use that for acne.'"

The condition that Chase was born with is caused by an abnormal elongation of a portion of DNA on the X chromosome. It is the most common inherited intellectual disability worldwide, affecting about 1 in 4,000 babies. It causes some cases of autism. Depending on the extent of the error, a child with fragile X can range from nonverbal to having communications skills that are mildly impaired. Epilepsy is common. Short-term memory deficits and very short attention spans can short-circuit academic progress.

It can seem like a train wreck of conditions — autism, attention deficit, bipolar disorder, anxiety and more — rolled into a single kid.

Yet now there's some genuine muscle pulling on the hope side of the equation, thanks to a confluence of parental activism, advances in brain science and luck.

"People haven't thought about what it would be like to reverse intellectual disability or mental retardation," says Dr. Randi Hagerman, medical director of UC Davis' MIND Institute, who ran the minocycline study in which Chase was enrolled. "We now think it may be possible."

It's a goal as controversial as it is ambitious. For decades, activists and parents championed inclusion for those with what was until recently called "mental retardation" (the preferred term now is "intellectual disability" or "developmental disability").

Somewhere along the way, many came to reject the idea that a "cure" was needed, or desirable. To suggest that intellectual disability is an illness crying out for a fix devalues and stigmatizes these children, they contended.

Advances in biomedical research have already begun putting that conviction to the test for families of those with Down syndrome.

In 2009, researchers at Stanford University School of Medicine and Packard Children's Hospital announced "a ray of hope" for those born with the condition. Working with mice bred to have the equivalent genetic error, they identified a faulty brain mechanism that disrupts the laying down of certain memories and, in turn, learning.

They also found that a readily available drug cocktail that boosts the brain chemical norepinephrine could compensate for the problem, enabling the mice to learn normally. With early use, the scientists suggested, such a drug might put a child born with Down syndrome on a normal cognitive trajectory.

Not all parents hailed this "ray of hope." Reacting to the news on a blog called Contrarian, Jenn Power, a Canadian mother of twin boys with Down syndrome, echoed the views of many who have been active in promoting the rights of those with intellectual disabilities.

"They do not need a needle in their brain to make them more functional, to help them find their car keys," she wrote. "What they need is a society that values what they have to offer."

After physicians recognized in Chase the classic profile of a fragile X child five years ago, he was treated with psychiatric medications, with limited results.

When puberty set in, his anxiety, aggression and repetitive behaviors escalated dramatically — along with his size and strength.

Heather Brown, a 38-year-old office manager for an electric contracting company, worried for his safety — and sometimes her own.

"I was dealing with hitting and kicking and throwing stuff," she said.

By then, she and her ex-husband, Chris, who lives in Carlsbad, had met UC Davis' Hagerman, who urged them to consider participation in her minocycline study. It went on to show that 70% of those with fragile X responded with significant improvement in language, behavior and cognitive function.

Minocycline's effectiveness in these early trials appears to be due to its suppression of a protein called MMP-9, which is overproduced in fragile X brains, derailing normal neural development. The antibiotic also tamps down inflammation in the brain. Both effects, amazingly, are incidental to the drug's antibiotic powers.

The drug's principal side effect in the studies is a graying of the teeth. A small number of patients developed blood signs suggestive of autoimmune inflammation, albeit with no associated symptoms.

Beyond minocycline, early trials are underway for three medications that inhibit a second protein that is overactive in fragile X brains and for a fourth drug, arbaclofen, that acts on yet another brain chemical. Arbaclofen appears from early drug-trial results to reduce the hyperactivity and hypersensitivity that are hallmarks of fragile X, and may help children with autism unrelated to fragile X.

Mark Bear, a neuroscientist at MIT's Picower Institute, says there's universal agreement that such drugs should produce the most dramatic changes in young children. But conducting early trials on very young children raises ethical and safety concerns, so they will focus on adults with fragile X for now.

Though this may limit the findings, "we have our fingers crossed that we'll still see substantial benefit," Bear said.

Many of the drugs considered promising for fragile X also have excited interest as treatments for a wider range of neurological conditions — stroke, spinal cord injury, multiple sclerosis, autism and Alzheimer's disease — a fact that will probably speed their path to market.

Chase, in the meantime, will continue to take minocycline, now prescribed off-label by Hagerman because the trial in which he participated is over.

"I'm sure people thought he might be a lost cause," his mother said of his situation before his treatment began. "I did wonder myself."

She said she didn't know what to make of today's talk of potential "cures." But now she sees a future in which her son might navigate the adult world — complete high school, have a job, an apartment, a girlfriend — with just a little help from family and social services.

"I'm definitely thinking differently," she said. "He's on a good path."