Protein May Make Up for Deficiency in Friedreich’s
 |
|
Grazia Isaya |
|
MDA research grantee Grazia Isaya at Mayo Clinic College of Medicine in Rochester, Minn., was part of a study that found that a protein called mitochondrial ferritin can substitute to a large extent for frataxin, the protein that’s deficient in Friedreich’s ataxia (FA).
This form of ferritin is located in the mitochondria, the energy-producing units of cells, as frataxin normally is. Its function is thought to be regulating iron levels in the mitochondria, which is the presumed function of frataxin.
In studies conducted in yeast cells and published in the Oct. 1 issue of Human Molecular Genetics, the investigators found that mitochondrial ferritin protected against damage associated with frataxin deficiency, which could mean that it might be relevant in the treatment of FA.
Additional studies in frataxin-deficient cells and in mice with FA will be needed to confirm these findings, Isaya says.
She adds, “Recent advances in the artificial manipulation of gene activity give hope that one day soon it will be possible to control protein production from specific genes. If mitochondrial ferritin compensates for frataxin deficiency in cells from mammals, then artificially increasing protein production from this gene will be a very attractive avenue for therapy of FA.”
Normal Mitochondrion
|
|
 |
Mitochondrion Without Frataxin
|
 |
In Friedreich’s ataxia, cells lack the frataxin protein, and iron builds up in the mitochondria. Recent research suggests that high levels of mitochondrial ferritin may compensate for frataxin deficiency.
|
|
Cell Death Prevention Studied in Congenital MD
 |
|
Jeffrey Miller |
|
The merosin-deficient form of congenital muscular dystrophy (CMD) might eventually be treated by interfering with a type of cell death known as apoptosis, according to MDA research grantee Jeffrey Boone Miller and colleagues at the Boston Biomedical Research Institute in Watertown, Mass.
The researchers bred mice lacking the protein merosin (also called laminin-alpha-2) and mimicking human merosin-deficient CMD. Some were then bred to overproduce a protein called Bcl-2, which protects against apoptosis, while others were bred not to produce a protein called Bax, which contributes to apoptosis. The findings were published in the Dec. 1 issue of the Journal of Clinical Investigation.
Both genetic interventions prolonged survival in these merosin-deficient mice. Inactivation of the gene for Bax also improved growth, decreased contractures (joint fixations), and improved the microscopic appearance of muscle cells in the mice.
Apoptosis results from a biochemical chain of events in which cells appear to “commit suicide.” These events are normal under certain circumstances, but widespread apoptosis in muscle cells after birth only occurs as part of a muscle-wasting disease.
“Much additional research is needed before we can fully understand the significance of our results,” Miller says. “We think the next step is to determine if drugs that inhibit cell death can lessen disease severity in laminin-alpha-2-deficient mice.” He notes that one such drug is minocycline, which is being tested in clinical trials in amyotrophic lateral sclerosis.
’Exon Skipping’ Treats Duchenne MD in Mice
 |
|
When an antisense molecule is given to mice with an abnormal “stop” signal in the genetic instructions for the dystrophin protein, it sticks to part of the instructions (yellow) and tells the cell to remove the section (exon) with the “stop” signal. The final genetic message has all the instructions for dystrophin except the small part that included the stop signal. The antisense-treated mice in these experiments made functional dystrophin.
|
|
Researchers at Genethon (a gene therapy research center) in Evry, France, and Cochin Hospital in Paris say they’ve successfully reversed signs of Duchenne muscular dystrophy (DMD) in the mdx mouse, which has a Duchenne-like muscle disease. Olivier Danos and colleagues published their findings in the Nov. 4 online issue of Science Express (www.sciencexpress.org).
The French researchers gave five mdx mice a molecular construction known as antisense. Antisense molecules prevent a cell from following (making “sense” of) specific genetic instructions. Scientists can direct antisense to stick to and block specific genetic targets.
Using an antisense molecule to coax a cell to ignore, or skip, an error (mutation) in a gene is called exon skipping. Exons are the parts of a gene that the cell normally reads and uses to make a protein. The goal in exon skipping is for the cell to skip a mutated exon and resume reading the exons that lie on the other side of it.
In these experiments, the antisense construction was tucked inside an adeno-associated virus, which served as a delivery vehicle, and injected into a leg artery in the mice.
The treated mouse muscles showed production of functional dystrophin, the protein needed but missing in boys with DMD. The protein was in its normal place near the muscle cell membrane and was attached to other proteins that normally assemble with it.
The mechanical properties of the treated muscles also improved.
A similar strategy is receiving support from MDA. One such grant is to Stephen Wilton at the University of Western Australia in Perth. Wilton’s group is using a compound known as F127 instead of a virus as an antisense delivery vehicle.
Clues About SMN Protein Promising for Spinal Muscular Atrophy
 |
|
Kay Davies |
|
Recent reports shed more light on the functions of the survival of motor neuron (SMN) protein and lend support to increasing production from the SMN2 gene as a potential treatment for spinal muscular atrophy (SMA).
A team led by Kay Davies at the University of Oxford (England) found that the protein Brunol3, which belongs to a group of “RNA binding proteins,” is found in the same places in nerve and muscle cells as is SMN, the protein needed but deficient in SMA. Davies has had MDA support for closely related work.
 |
|
Thomas Prior |
|
The researchers, who published their findings in the November issue of Neuromuscular Disorders, speculate that the two proteins may work together to help process RNA, the genetic message made from DNA.
They also hypothesize that their actions could play roles both in development of the nervous system and in maintaining the connections among cells.
“An understanding of why motor neurons are vulnerable to the lack of SMN in patients will help us devise ways to target an effective treatment for the disease in the future,” Davies says.
In another study, MDA grantees found that people with five copies of the SMN2 gene apparently withstand a total loss of the gene known as SMN1. Until now, researchers thought at least one intact SMN1 gene was necessary to prevent the development of SMA.
 |
|
Kathryn Swoboda |
|
MDA grantees Thomas Prior at Ohio State University in Columbus and Kathryn Swoboda at the University of Utah in Salt Lake City report in the Oct. 15 issue of the American Journal of Medical Genetics that even a complete lack of the SMN1 gene doesn’t necessarily lead to SMA if a person has several SMN2 genes to act as reserve troops.
Previously, it’s been found that people lacking a functioning SMN1 gene but with three or four copies of SMN2 usually develop relatively mild (type 3) SMA, while those with one or two copies develop more severe (type 1 or 2) SMA.
These findings provide additional support for current research that aims to treat SMA by increasing protein production from the SMN2 gene, Prior says.
“Now we know how much SMN2 we need — about five genes’ worth.”
CLINICAL TRIALS AND STUDIES
National Initiative on Duchenne MD Families Conducting Survey
The U.S. Centers for Disease Control and Prevention and the American Association of Medical Colleges are sponsoring a study of the impact of Duchenne muscular dystrophy (DMD) on families and on what services affected families are receiving. The investigators plan to survey 1,500 families in which at least one person has DMD.
Investigators say the survey questions will take two to three hours to answer.
For information, call project coordinator Marie Ritzo at (800) 343-5878, or write to the National Initiative for Families with Duchenne, Children’s National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010.
Heart Problems Seen in Type 2 Myotonic MD
 |
|
John Day |
|
Researchers at the University of Wurzburg in Germany say they’ve found evidence that people with type 2 myotonic dystrophy (MMD2) can have subtle heart problems long before symptoms appear and even before changes can be detected on routine cardiac exams.
The investigators, who published their findings in the November issue of Muscle & Nerve, studied 11 people with MMD2 and compared them to a group of healthy subjects. They examined the participants’ hearts with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS).
In people of all ages with MMD2, MRS showed evidence of reduced energy production in cardiac muscle tissue compared to the healthy group. In older MMD2 patients, MRI examination revealed moderate enlargement and dilation of the left ventricle, which the researchers say indicates early, mild cardiomyopathy (cardiac muscle disease).
John Day, a neurologist who directs the MDA clinic at Fairview University Medical Center in Minneapolis and sees many patients with MMD2, says he and his colleagues have detected abnormalities in cardiac muscle function and in heartbeat rhythms in many people with this disorder.
“Involvement of the heart can be clinically important and potentially life-threatening, dictating that patients receive regular checkups and thorough investigation of any cardiac symptoms,” Day says.
“The new findings support the impression that type 2 myotonic dystrophy might cause a primary [initial] cardiomyopathy, in addition to altering heart function by development of arrhythmias and conduction defects [heartbeat irregularities].”
Higher Anxiety Found in People With MG
Milind Kothari at Pennsylvania State University College of Medicine in Hershey, and colleagues, have conducted a study showing that anxiety may be higher than average, even for people with chronic disease, in those with myasthenia gravis (MG).
The investigators, who published their results in the September issue of the Journal of Clinical Neuromuscular Disease, gave self-administered questionnaires to 69 people with MG.
The questionnaire, which included a standardized test called the Beck Anxiety Inventory, showed that 55 percent had scores suggesting they were experiencing anxiety. Some 40 percent were judged mildly anxious, 12 percent moderately anxious, and 3 percent severely anxious.
The authors cite another study showing that the prevalence of anxiety in the general population is about 7.7 percent.
The MG survey didn’t ask subjects what medications they were taking or formally assess variations in disease severity.
The investigators say that depression is known to be common in people with chronic medical conditions but that anxiety hasn’t been widely recognized.
CMT Database Project Seeks Participants
Researchers at Wayne State University in Detroit are compiling a database about Charcot-Marie-Tooth disease (CMT) and are asking people with this disorder to fill out questionnaires about their medical and family histories.
The North American CMT Database, funded in part by MDA, is designed to collect information about CMT that will help investigators to better understand the condition and develop treatments for it.
Data that can’t be traced back to participants will be available to researchers. Identifying information will be released only with a participant’s written consent.
Forms are available online at http://www.med.wayne.edu/neurology/clin_programs/Labs/CMT/index.htm.
You can also contact Carly Siskind at (313) 577-5273 or csiskind@med.wayne.edu.
Cardiac and Respiratory Impairment High in LGMD2I
Kate Bushby at the Institute of Human Genetics in Newcastle upon Tyne, England, and colleagues in Britain, Germany and Canada, recently found a high incidence of involvement of the heart or respiratory system in 38 people with type 2I limb-girdle muscular dystrophy (LGMD2I), a form of MD caused by mutations in the gene for fukutin-related protein.
The investigators, who published their findings in the November issue of Annals of Neurology, found that 21 of the 38 subjects (55 percent) had either possible or definite cardiac involvement. Of the 36 participants whose respiratory function was measured, 13 (36 percent) had moderate respiratory impairment, and three (8 percent) had severe respiratory impairment.
The authors write, “This multicenter study confirms that patients with LGMD2I are at risk of cardiac and respiratory failure that will progress with time....
“Our data also indicate that treatment with standard cardiac therapy [ACE inhibitor drugs and diuretics were prescribed for some patients] is effective in delaying progression.... Nonetheless, some patients are likely to show progression of their cardiac disease, necessitating cardiac transplantation.”
The authors also note, “There was no absolute correlation between skeletal muscle weakness and cardiomyopathy [cardiac muscle disease] or respiratory insufficiency.”
