The Skinny on Breakthrough Myelin Sheath Disorders

In patients with multiple sclerosis, cerebral palsy, and other rare genetic disorders known as leukodystrophies, the myelin sheath – the fatty covering that acts as an insulator around nerve fiber is progressively destroyed. Without this vital insulation, brain impulses to the rest of the body are lost leading to debilitating symptoms such as loss of muscle tone, movement, gait, speech, vision, hearing, ability to eat, and behavioral changes.

So we were very excited to learn that researchers at Case Western Reserve School of Medicine have discovered a technique that can directly convert skin cells to the type of brain cells destroyed in myelin disorders.

This amazing new technique involves 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,’” explains Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine “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, rapidly generated billions of these induced OPCs (iOPCs). They also 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. “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.

These are exciting times. The progression of stem cell biology is providing therapeutic opportunities that a decade ago would not have been thought possible. As always SRxA’s Word on Health, will bring you further developments on this story as soon as they’re released.

Be Still My Beating Heart! – Monty Python and the Holy Grail

Look up the term myocardial infarction (MI) in any medical dictionary and the definition will be something along the lines of –  the changes to the myocardium (heart muscle) that occur due to the sudden deprivation of circulating blood. The main change being necrosis, or death of myocardial tissue. Death of myocardial tissue.  As in dead, as in non-viable, as in beyond repair. Kind of reminds me of the infamous Monty Python Dead Parrot sketch… “Passed on! No more! Ceased to be! Expired and gone to meet ‘is maker!”….but I digress.

Fast forward from the British humor of December 1969 to an astonishing paper presented in Britain in April 2012  at the Frontiers in CardioVascular Biology meeting. In a keynote lecture, Dr Deepak Srivastava outlined results that have been described as a “game changer” with the potential to revolutionize the treatment of MI.   Srivastava used viral vectors to deliver genes directly into the hearts of adult mice that had experienced an MI. In his original “proof of principle” study, Srivastava was able to show that all that was needed for the direct  reprogramming of fibroblasts (a major component of scar tissue) into myocytes (the heart muscle cells responsible for  beating)  was the delivery of three genes.  The work , which took place in a Petri dish, was considered groundbreaking since it showed for the first time that unrelated adult cells could be reprogrammed from one cell type to another without having to go all the way back to a stem cell state. “Our ultimate hope is that, during the acute period following MI, patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the “scar” into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives,” explained Srivastava.

Healthy heart tissue is composed of a mixture of several kinds of cells, including cardiomyocytes, which provide beating muscle and cardiac fibroblasts that provide architectural support to the myocytes. “When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration,” says Srivastava.  Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar. At first, the process can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later, difficulties arise when the fibrotic scar doesn’t contract like the muscle it has replaced. “Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death,” said Srivastava.

One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart.  Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury.  But many hurdles have been encountered including getting cells to integrate with neighboring cells in the heart, and there have been concerns that residual “rogue” cells could persist with the potential to keep dividing and give rise to tumors.

Srivastava, a pediatric cardiologist, explained how he got ahead of the game by “leveraging” knowledge from his work in embryo hearts. Over the past 15 years the focus of Srivastava’s lab has been to identify genetic factors responsible for the formation of embryonic hearts. From this work, his team identified 14 key genes that they felt were the major “on/off” switches for cardiac genetic programming. In this original study they were able to whittle things down to the three factors that were indispensible. The team then injected fibroblasts that had the three genes inserted directly into the scar tissue of mice.  They were able to show the fibroblasts differentiated into cardiomyocyte-like cells. In the latest study  they were able to take the process one step further by injecting a viral vector encoding the  3 genes directly into the scar tissue of mice who had just experienced an MI. “With these studies we’ve obtained even better results showing that the fibroblasts become more like cardiomyocytes and functionally couple with their neighbors. They could beat in synchrony and improve the function of the heart,” said Srivastava.

The next step will be to test the direct injection approach in a larger animal, such as a pig, whose heart is similar in size to a human.  But a big question remains “will the same combination of genes work in human hearts?” SRxA’s Word on Health will be watching and waiting. In the meantime…it’s back to Monty Python!

The battle of bone marrow versus breast cells

Forget who’ll win the X-Factor, Dancing with the Stars or even the Superbowl.  SRxA’s Word on Health brings you hot, breaking news from a world class content of microscopic mobility. We have to admit we almost missed this story and want to thank one of our regular readers, Jeff Boulier, for bringing it to our attention.

In an astonishing fear of athleticism, a line of bone marrow stem cells from Singapore beat out dozens of competitors to claim the title of the world’s fastest cells. They whizzed across a petri dish at the breakneck speed of 5.2 microns per minute — or 0.000000312 kilometers per hour!

Results of the World Cell Race were announced last week at the annual meeting of the American Society for Cell Biology in Denver, Colorado. Organizers declared the competition a success: “50 participating labs all over the world! 70 cell lines recorded! Without a single dollar to fund the project!” said Manuel Théry from Institut de Recherche en Technologies et Sciences pour le Vivant (iRTSV) in Grenoble, France. Behind the fun is a serious goal: looking at how cells move. Ultimately, it is cell migration that helps embryos and organs to develop and allows cancer to spread. The contest provided a lot of new information.  For example, stem cells and cancer cells seem to be faster than their mature and healthy counterparts. Rather than actually racing the cells, teams shipped frozen cells to designated laboratories in Boston, London, Heidelberg, Paris, San Francisco, and Singapore. Thawed cells were placed in wells containing “race tracks”. Digital cameras then recorded the cells for 24 hours to determine the fastest run down the track for each cell line. In total, about 200 cells of each cell type were timed to see how long it took the fastest individual cell of each type to reach the end of its track.

The key to victory?  According to Théry, who co-organized the race with colleagues from Institut Curie in Paris, the secret is to  avoid changing direction.  Cells that went back and forth along the track took longer to finish. Coming in second were a line of breast epithelial cells from France, with third place going to the same cell type tweaked to reflect patterns observed in cancerous cells. They clocked 3.2 and 2.7 microns per minute respectively.  Finishing fourth, at a still respectable 2.5 microns per minute, was the UK team of cultured human skin cells derived from patients with a rare genetic skin disorder. The winners received Nikon digital cameras and coveted World Cell Race medals.

What next?  Cellular showdowns in swimming and weightlifting or perhaps a full scale Cyto-lympics!

Stemming the Damage from Stroke?

UK based stem cell technology company ReNeuron announced this week that it has treated its first patient in the Phase I PISCES (Pilot Investigation of Stem Cells in Stroke) study.

The trial is designed to recruit a total of 12 men (> 60 years of age). Participants will receive a direct injection of ReN001 cells into the affected brain region between six and 24 months following their stroke. While the study will primarily evaluate the safety of the stem cells, a number of efficacy measures will also be evaluated over two years of follow-up.

The first patient was treated with the stem cells at the Institute of Neurological Sciences, Southern General Hospital, in Glasgow, Scotland; and was safely discharged two days after the straightforward neuro-surgical procedure. Southern General is one of Europe’s most innovative and well-recognized stroke treatment centers and is perhaps best known as the place where the Glasgow Coma Scale was developed.

Assuming a satisfactory independent Data Safety Monitoring Board review of the first patient’s progress in December 2011, the additional patients will be treated shortly thereafter. Subject to satisfactory safety data ReNeuron intends to pursue an accelerated clinical development pathway with ReN001, focusing on particular stroke patient groups who are expected to most benefit from the therapy.

Principal investigator Professor Keith Muir suggested that “if the therapy works it may allow new nerve cells to grow or regeneration of existing cells and actual recovery of function in patients who would not otherwise be able to regain function.”

Stroke is the third largest cause of death and the single largest cause of adult disability in the developed world.  It occurs when blood flow leading to, or in, the brain is blocked (ischemic stroke) or a blood vessel in the brain ruptures (hemorrhagic stroke). This results in damage to the nerve cells in the brain and a loss of bodily functions.

Stroke is the single largest cause of adult disability in the developed world. Over 700,000 people suffer a stroke each year in the US, of which, approximately 80% are ischemic in nature.

In the US, the annual direct and indirect costs of stroke are estimated to be in excess of $50 billion.

The type of stroke treatment a patient should receive depends on the stage of disease:

• Prevention – treatments to prevent a first or recurrent stroke are based on treating associated risk factors, e.g. high cholesterol, smoking and diabetes
• Immediately after the stroke – treatments attempt to arrest a stroke whilst it is happening by dissolving the blood clot that has caused the infarct
• Post stroke rehabilitation – aims to improve both functional and cognitive recovery in the patient weeks or months after the event.

ReN001 stem cell therapy seeks initially to target ischemic stroke patients in the third stage.  These patients constitute approximately one half of stroke survivors.

SRxA’s Word on Health will be following this story and will bring you updates as they happen.

Spinal Cord Injury therapy – one small step closer

Back in August 2010, Word on Health brought you news that the FDA had given the green light for a stem cell therapy trial.

Given the enormous ethical and regulatory hurdles surrounding this controversial topic, we take our hats off to Geron Corporation who, on Monday, announced the enrolment of the first patient.

The primary objective of the Phase I study is to assess the safety and tolerability of the stem-cell therapy GRNOPC1 in patients with recent thoracic spinal cord injuries. The therapy is injected directly into the injured area and is hoped to restore spinal-cord function by triggering the production of myelin-producing cells, potentially allowing for new movement.

Spinal Cord Injury is caused by trauma to the spinal cord that results in loss of functions such as movement, sensation and bowel or bladder control. Every year approximately 12,000 people in the U.S. sustain spinal cord injuries. The most common causes are automobile accidents, falls, gunshot wounds and sports injuries.

The initiation of this Phase I study is thought to represent the first publicly known use of embryonic stem cells in humans.

According to Geron’s President and CEO, Thomas B. Okarma, Ph.D., M.D. “Initiating the GRNOPC1 clinical trial is a milestone for the field of human embryonic stem cell-based therapies. When we started working on this in 1999, many predicted that it would be a number of decades before a cell therapy would be approved for human clinical trials.”

In order to participate in the study, patients must be newly injured and receive the therapy within 14 days of the injury. The company has said it plans to enroll between eight and 10 patients in the US.

The trial is expected to take about two years to complete. Word on Health will be watching closely and will bring you further news as it breaks.  In the meantime we’d love to hear from you about your thoughts on this.

21st Century Medicine promises new cures

More than 400 leaders in the field of regenerative medicine from across the world gathered last week in North Carolina at the 1st annual Translational Regenerative Medicine Forum.

Regenerative Medicine focuses on:

·         Medical devices and artificial organs

·        Tissue engineering and biomaterials

·         Cellular Therapies

·         Clinical Translation

The meeting covered best practices and business models to bring new therapies to patients Speakers also discussed the challenges of this emerging medical field, including obtaining funding. Robert N. Klein, of the California Institute for Regenerative Medicine, talked about that state’s successful referendum to fund stem cell research with state-issued bonds. He compared state investment in scientific research to investment in roads and other infrastructure. “We are used to funding physical capital. We have to realize that in the 21st century it is appropriate to fund intellectual capital.”

Andrew von Eschenbach, M.D., of the Center for Health Transformation, said that the promise of regenerative medicine demands a paradigm shift from treating disease to restoring health.

Although this may sound like a distant dream a lot of research is being undertaken.

“Regeneration is one of our top priorities,” said Alan Lewis, Ph.D., President and CEO of the Juvenile Diabetes Research Foundation International, “the organization has invested $60 million in the past few years on research to regenerate islet cells, the cells in the pancreas that produce insulin”.

Col. Janet R. Harris, Ph.D., M.S.N., from the U.S. Army Medical Research and Materiel Command, talked about a $85 million federally funded project to apply the science of regenerative medicine to battlefield injuries. “We’ve been very pleased with the progress we’re seeing,” she said. “Only two years into the grant, 13 clinical trials are being funded.”

Word on Health wonders which will come first, the Six Billion Dollar Man or the Bionic Woman?!?

We invite you to have your say.