Posts tagged myelin disorders

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)

A study out today in the journal Cell Stem Cell shows that human brain cells created by reprogramming skin cells are highly effective in treating myelin disorders, a family of diseases that includes multiple sclerosis and rare childhood disorders called pediatric leukodystrophies.

The study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. In this instance, the researchers utilized cells crafted from human skin and transplanted them into animal models of myelin disease.

"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells."

The discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by the loss of a specific cell population in the central nervous system called myelin. Like the insulation found on electrical wires, myelin is a fatty tissue that ensheathes the connections between nerve cells and ensures the crisp transmission of signals from one cell to another. When myelin tissue is damaged, communication between cells can be disrupted or even lost.

The most common myelin disorder is multiple sclerosis, a condition in which the body’s own immune system attacks and destroys myelin. The loss of myelin is also the hallmark of a family of serious and often fatal diseases known as pediatric leukodystrophies. While individually very rare, collectively several thousand children are born in the U.S. with some form of leukodystrophy every year.

The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.

However, several obstacles have thwarted scientists. One of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development.

"Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."

Another challenge has been identifying the ideal source of these cells. Much of the research in the field has focused on cells derived from tissue-specific and embryonic stem cells. While research using these cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common.

The discovery in 2007 that human skin cells could be “reprogrammed” to the point where they returned to a biological state equivalent of an embryonic stem cell, called induced pluripotent stem cells, represented a new path forward for scientists. Because these cells – created by using the recipient’s own skin – would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promised an abundant source of material from which to fashion the cells necessary for therapies.

Goldman’s team was the first to successfully master the complex process of using hiPSCs to create OPCs. This process proved time consuming. It took Goldman’s lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.

Once they succeeded in identifying and purifying OPCs from hiPSCs, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.

They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.

"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," said Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."

The next stage in evaluating these cells – clinical studies – may not be long in the offing. Goldman, along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo, are preparing to launch a clinical trial using OPCs to treat multiple sclerosis. This group, titled the Upstate MS Consortium, has been approved for funding by New York State Stem Cell Science (NYSTEM). While the consortia’s initial study – the early stages of which are scheduled to begin in 2015 – will focus cells derived from tissue sources, Goldman anticipates that hiPSC-derived OPCs will eventually be included in this project.

(Source: eurekalert.org)