Posts tagged leukodystrophies

Researchers in Spain have found that a drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. They believe that their findings may be relevant to other neurodegenerative diseases.  A Phase II trial will be starting shortly. The research is published simultaneously on line in the journal Brain.

A drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. This is an important step along the road to the development of a therapy for the human disease for which current treatment options are scarce and only partially effective, the annual conference of the European Society of Human Genetics will hear tomorrow (Sunday).

Professor Aurora Pujol, a research professor for the Catalan Government Research Body ICREA, working as Director of the Neurometabolic Diseases Laboratory at IDIBELL, Barcelona, Spain, investigated the role of mitochondria, the power plant of the cell, in adrenoleukodystrophy, a disease caused by the inactivation of the ABCD1 transporter of fatty acids in peroxisomes.  This inactivation leads to the accumulation of fatty acids in organs and blood plasma, and causes spinal cord degeneration.

“ABCD1 is a protein located in the peroxisomes, compartments of the cell that detoxify chemicals and lipids, and thus the implication of mitochondria in such a disease was not obvious.  But we knew from recent research that oxidative stress – where there is increased production of chemically active oxygen-containing molecules, and also significant decrease in the effectiveness of the body’s antioxidant defences – was involved.  We also knew that bioenergetic failure appeared before disease symptoms.  We therefore decided to investigate the role of the mitochondria”, Professor Pujol will say.

The group of diseases known as leukodystrophies are characterised by progressive loss of the myelin sheath, the fatty covering that acts as an insulator around nerve fibres.  Damage to the myelin sheath impairs the conduction of signals in the affected nerves and leads to locomotor problems. 

“We knew that early oxidative damage and bioenergetic dysfunction underlay the late onset degeneration of nerve fibres observed in the mouse model of X-linked adrenoleukodystrophy (X-ALD), the most frequently inherited leukodystrophy, so we looked at mitochondria for further clues.  We found that the X-ALD mice showed a loss of mitochondria at 12 months of age, prior to disease symptoms, so this could not be a consequence of the disease, but rather a contributing factor.  We also knew that the pathway involved in the mitochondrial loss could be treated by the use of the diabetes drug pioglitazone, so we decided to test its effect in the mice”, Professor Pujol will say.

Pioglitazone halted the nerve fibre degeneration by preventing the loss of mitochondria, and inhibiting metabolic failure and oxidative stress in the treated mice, and hence also halted locomotor disabilities.   The researchers were able to prove this both through analysis of spinal cords post mortem, and in vivo by putting the mice through a number of physical tests.

Although X-ALD is a relatively rare disease  with a minimum incidence of 1 in 17 000 males, there are other neurodegenerative disorders caused by myelin sheath degeneration, for example multiple sclerosis, and many others where impaired bioenergetics combined with oxidative stress and degeneration of axons are known to be involved.  The latter category of disease includes Parkinson’s, Huntington’s, and Alzheimer’s.  “It is possible that our findings may be relevant to these conditions as well,” says Professor Pujol.

“Following on from these promising results, together with Professor Patrick Aubourg from the Hôpital Bicêtre, Paris, we will shortly be starting a multi-centre phase II clinical trial of pioglitazone in adult patients suffering from a late onset variant of adrenoleukodystrophy.   Our research has shown that it will be feasible to monitor the biological effects of the drug by looking for biomarkers of oxidative damage in blood cells or plasma.  We are happy to have made a contribution to finding a simple and effective treatment to a group of devastating diseases”, she will conclude.

(Source: alphagalileo.org)

Neuroscientists at UB’s Hunter James Kelly Research Institute show how turning down synthesis of a protein improves nerve, muscle function in common neuropathy.

A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo’s Hunter James Kelly Research Institute and their colleagues in Italy and England.

The institute is the research arm of the Hunter’s Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe Leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies.

Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin.

The new findings were published online earlier this month in The Journal of Experimental Medicine.

They may have relevance for other diseases that result from misfolded proteins, including Alzheimer’s disease, Parkinson’s, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.

The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy.

CMT neuropathies are common, hereditary and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.

“It’s possible that our finding could lead to the development of an effective treatment not just for CMT neuropathies but also for other diseases related to misfolded proteins,” says Lawrence Wrabetz, MD, director of the institute and professor of neurology and biochemistry in UB’s School of Medicine and Biomedical Sciences and senior author on the paper. Maurizio D’Antonio, of the Division of Genetics and Cell Biology of the San Raffaele Scientific Institute in Milan is first author; Wrabetz did most of this research while he was at San Raffaele, prior to coming to UB.

The research finding centers around the synthesis of misfolded proteins in Schwann cells, which make myelin in nerves. Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Many CMT neuropathies are associated with mutations in a gene known as P0, which glues the wraps of myelin together. Wrabetz has previously shown in experiments with transgenic mice that those mutations cause the myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.

When cells recognize that the misfolded proteins are being synthesized, cells respond by severely reducing protein production in an effort to correct the problem, Wrabetz explains. The cells commence protein synthesis again when a protein called Gadd34 gets involved.

“After cells have reacted to, and corrected, misfolding of proteins, the job of Gadd34 is to turn protein synthesis back on,” says Wrabetz. “What we have shown is that once Gadd34 is turned back on, it activates synthesis of proteins at a level that’s too high—that’s what causes more problems in myelination.

“We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that’s what causes some neuropathies,” says Wrabetz. “We’ve shown that if we just reduce Gadd34, we actually get better myelination. So, leaving protein synthesis turned partially off is better than turning it back on, completely.”

In both cultures and a transgenic mouse model of CMT neuropathies, the researchers improved myelin by reducing Gadd34 with salubrinal, a small molecule research drug. While salubrinal is not appropriate for human use, Wrabetz and colleagues at UB and elsewhere are working to develop derivatives that are appropriate.

“If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases as well,” says Wrabetz.

And while CMT is the focus of this particular research, the work is helping scientists at the Hunter James Kelly Research Institute enrich their understanding of myelin disorders in general.

“What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe’s,” Wrabetz says. “We’d like to build a foundation and answer basic questions about where and when toxicity in diseases begin.”

The misfolded protein diseases are an interesting and challenging group of diseases to study, he continues. “CMT, for example, is caused by mutations in more than 40 different genes,” he says. “When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism: this problem of Gadd34 turning protein synthesis on at too high a level could be one unifying mechanism. The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer’s, Parkinson’s, Type 1 diabetes and the other diseases caused by misfolded proteins.”

(Source: buffalo.edu)

Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy

Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.

This discovery appears today in the journal Nature Biotechnology.

This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.

The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.

“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”

In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”

This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”

(Source: newswise.com)