Using injections of a small derivate of the protein insulin-like growth factor-1 (IGF-1), scientists at Whitehead Institute for Biomedical Research and MIT's Picower Institute for Learning and Memory have successfully treated a mouse model of the devastating neurological disorder Rett syndrome.
Rett syndrome is an inherited disease affecting one of 10,000 girls born. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be mediated with prescription drugs, but no cure or truly effective treatment for the disease exists.
In a study appearing in the February issue of the Proceedings of the National Academies of Sciences, researchers showed that daily injections of an active fragment of IGF-1 in mice that expressed Rett-syndrome like symptoms could significantly reduce movement and respiratory irregularities. Although treated mice were not cured, the outcome is reason for optimism.
"This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," says Whitehead Member Rudolf Jaenisch, whose lab collaborated with the lab of MIT and Picower scientist Mriganka Sur in the research.
In approximately 85% of girls with Rett syndrome, the disease is caused by loss of function of the MeCP2 gene, which is highly expressed during nerve cell maturation. Lack of MeCP2 expression impedes nerve cell growth, keeping the cells from forming projections, called spines, which are used for nerve-cell-to-nerve-cell communication. Recent genetic studies have shown that in mice with blocked MeCP2 expression, turning MeCP2 back "on" nudges the mice towards normal movement and lifespan—an indication that the disease could be reversible.
Although researchers have known which gene causes the vast majority of Rett syndrome cases, they have until now been unable to promote nerve cell maturation through administration of a drug, protein, or small molecule.
While researchers in Sur's lab had discovered that increased brain levels of IGF-1 promoted maturation of synapses, the connections between nerve cells that are the basis for brain functions, Emanuela Giacometti, a graduate student in Jaenisch's laboratory, was theorizing that IGF-1 might also increase the nerve cell spines in the lab's mouse model of Rett syndrome. Such mice lack the MeCP2 gene and at four to six weeks display symptoms quite similar to those in girls with Rett Syndrome, including difficulty walking, lethargy, and breathing and heart rhythm irregularities.
In a collaboration with the Sur lab to test how IGF-1 might affect these mice, Giacometti administered to two-week-old Rett mice daily injections of IGF-1 fragment. At six weeks, treated mice were significantly more active, had more regular breathing, and had more normal, regular heart rhythms than did untreated mice. In addition, the brains of treated mice were heavier and showed more nerve cell spines.
"Although the treated mice get better and their symptoms don't progress as fast as they normally would, the treated mice still get the symptoms. So it's definitely not a cure, but it could be a co-therapy," Giacometti says.
Sur is also excited by the prospect of finding a drug treatment for Rett syndrome and other forms of autism. IGF1 is approved by the US Food and Drug Administration (FDA) to treat severe IGF-1 deficiency. "This represents a way forward towards clinical trials and a mechanism-based treatment for Rett Syndrome. We very much hope our research can offer some help for the patients who have this terrible disorder
Monday, March 2, 2009
Thursday, January 15, 2009
Drugs Hint At Potential Reversal Of Autism
Scientific researchers can spend years in the lab on obscure topics, like how a sea slug remembers or how a fruit fly sees color. But every now and then, a basic scientist makes a discovery that changes human lives.
Mark Bear, who directs the Picower Institute for Learning and Memory at MIT, is one of those basic scientists. He's discovered a system in the brain that could change the lives of thousands of people with the genetic disorder known as Fragile X Syndrome.
Fragile X is a mutation on the X chromosome that can cause mental retardation and autism. Until now, there has been no treatment.
But Bear discovered that the mutation responsible for Fragile X appears to disrupt a system in the brain that regulates synapses — the connections between brain cells. He says the system works a bit like a car.
"You really need both the accelerator and the brake to properly function," Bear says. "In the case of Fragile X, it's like the brakes are missing. So even tapping the accelerator can have the car careening out of control."
Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.
The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect.
The implications for people with Fragile X are huge. If the drugs work, people with the disorder could see their IQs rise and their autism diminish.
"It's a dream come true to think that we have the prospect of having gone from really basic science discovery to a potential treatment," Bear says.
Bear's research was funded in part by a group called FRAXA. Katie Clapp and her husband, Michael Tranfaglia, started the group in the early 1990s as a way to help their son Andy, who has Fragile X Syndrome.
Clapp says she now has reason to hope that Andy, who is now 19, can get better.
"We're not expecting a miracle, or to make up for his 19 years of development," she says. "But if we can watch improvement happen, that's a dream."
Mark Bear, who directs the Picower Institute for Learning and Memory at MIT, is one of those basic scientists. He's discovered a system in the brain that could change the lives of thousands of people with the genetic disorder known as Fragile X Syndrome.
Fragile X is a mutation on the X chromosome that can cause mental retardation and autism. Until now, there has been no treatment.
But Bear discovered that the mutation responsible for Fragile X appears to disrupt a system in the brain that regulates synapses — the connections between brain cells. He says the system works a bit like a car.
"You really need both the accelerator and the brake to properly function," Bear says. "In the case of Fragile X, it's like the brakes are missing. So even tapping the accelerator can have the car careening out of control."
Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.
The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect.
The implications for people with Fragile X are huge. If the drugs work, people with the disorder could see their IQs rise and their autism diminish.
"It's a dream come true to think that we have the prospect of having gone from really basic science discovery to a potential treatment," Bear says.
Bear's research was funded in part by a group called FRAXA. Katie Clapp and her husband, Michael Tranfaglia, started the group in the early 1990s as a way to help their son Andy, who has Fragile X Syndrome.
Clapp says she now has reason to hope that Andy, who is now 19, can get better.
"We're not expecting a miracle, or to make up for his 19 years of development," she says. "But if we can watch improvement happen, that's a dream."
Wednesday, January 14, 2009
School gets 'a lot of credit' for autistic boy's growth
by DAVID WENNER, Of The Patriot-News
Tuesday January 13, 2009, 11:57 PM
Helen Reyes knew cancer would kill her. But the single mom was most afraid of what would happen to her son, L.J.
L.J. has fragile x syndrome, which is similar to autism. He'll probably never be completely independent.
Reyes knew she wouldn't be around to fend for L.J. So she latched onto a dream.
She dreamed of an institution such as the one depicted in the movie "Rain Man," in which Dustin Hoffman played an autistic man.
She pictured L.J. surrounded by trees and lawns. She imagined gentle caregivers who would protect her son, who was 13 when she died in 2005.
As often happens with dreams, it didn't come true. Yet she might be smiling.
L.J., now 16, lives near Halifax in a house overlooking a valley. He goes to Upper Dauphin High School, attending a program that focuses on making him as independent as possible.
His classroom contains a replica of an apartment, where students learn about cooking and cleaning and laundry.
"I think it has worked out great," said Beth Lehman, his legal guardian. "I give the school a lot of credit."
Through the school, he has worked at a church preparing meals for the elderly, and at a local grocery store.
He's more composed and makes more eye contact than he did a few years ago, Lehman said. He visits his grandmother, Johanne Kohl of Steelton, and his uncle, who lives in Philadelphia.
Sherry Gaglione of West Hanover Township was a close friend of Helen Reyes and has known L.J. since he was a little boy. She keeps in touch with Lehman and L.J.
"I couldn't be more happy for him. He's adjusting well. Beth is like his second mom," Gaglione said.
Tuesday January 13, 2009, 11:57 PM
Helen Reyes knew cancer would kill her. But the single mom was most afraid of what would happen to her son, L.J.
L.J. has fragile x syndrome, which is similar to autism. He'll probably never be completely independent.
Reyes knew she wouldn't be around to fend for L.J. So she latched onto a dream.
She dreamed of an institution such as the one depicted in the movie "Rain Man," in which Dustin Hoffman played an autistic man.
She pictured L.J. surrounded by trees and lawns. She imagined gentle caregivers who would protect her son, who was 13 when she died in 2005.
As often happens with dreams, it didn't come true. Yet she might be smiling.
L.J., now 16, lives near Halifax in a house overlooking a valley. He goes to Upper Dauphin High School, attending a program that focuses on making him as independent as possible.
His classroom contains a replica of an apartment, where students learn about cooking and cleaning and laundry.
"I think it has worked out great," said Beth Lehman, his legal guardian. "I give the school a lot of credit."
Through the school, he has worked at a church preparing meals for the elderly, and at a local grocery store.
He's more composed and makes more eye contact than he did a few years ago, Lehman said. He visits his grandmother, Johanne Kohl of Steelton, and his uncle, who lives in Philadelphia.
Sherry Gaglione of West Hanover Township was a close friend of Helen Reyes and has known L.J. since he was a little boy. She keeps in touch with Lehman and L.J.
"I couldn't be more happy for him. He's adjusting well. Beth is like his second mom," Gaglione said.
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