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.

The Tangled Webs We Weave

Growing fresh blood vessels is a much fantasized goal of biomedical engineers. It’s probably also a fantasy of dialysis patients, hemophiliacs and others with medical conditions that necessitate regular venipuncture and whose veins are a mess from being breached several times a week.

To date, most approaches for growing blood vessels have involved coaxing human cells, either from donors or the patient themselves to manufacture connective tissue. One of the biggest challenges however has been to make the tissues develop into vein shaped vessels.  Some researchers have started with flat sheets of this tissue which they then roll into tubes. Others have used tubular molds. Typically, however, the scaffolding is eventually destroyed by the body’s immune system.

Now one company –  Cytograft Tissue Engineering, is trying a technique that made us look twice. They’re weaving the vessels from human thread that’s been created by spinning thin strips of cultured connective tissue.

The hope is that these woven structures could be easier to mass-produce than the tubes made with other techniques.

“A long time ago we decided we were going to make strong tissues without any scaffolding,” says Nicolas L’Heureux, Cytograft’s cofounder and chief scientific officer. “Once you get it in the body, your body doesn’t see it as foreign.”

The company developed the “human textile” idea from earlier work using sheets of biological material to reconstruct blood vessels. Researchers grow the human skin cells in a flask under conditions that encourage the cells to lay down a sheet of extracellular matrix – a structural material that makes up connective tissue. They then harvest the sheets from the culture flasks and then slice the sheets into thin ribbons that can be spooled into threads which can be used by automated weaving and braiding machines to create three-dimensional structures that do not require fusing.

Weaving 48 strands of human connective tissue into a tube

“Creating textiles is an ancient and powerful technique, and combining it with biomaterials is exciting because it has so much more versatility than the sheet method,” says Christopher Breuer, a surgeon, scientist, and tissue engineer at the Yale School of Medicine. “The notion of making blood vessels or more complex shapes like heart valves, or patches for the heart, is much easier to do with fibers. There is no limit to the size or shapes that you can make.”

In other words, the biological strands could be used to weave blood vessels, patches and grafts that a patient’s body would readily accept for almost any kind of wound repair or reconstruction.

Cytograft has not yet tested its woven blood vessels in humans, but preclinical dog work has shown that the grafts are resistant to puncture damage and that very little blood leaks from the weave.

Furthermore, the implants remain intact after months. That’s partly because Cytograft’s implants contain no cells. Though the company’s earlier implants were made of extracellular matrix produced from a patient’s own cells, they now harvest the material from cells unrelated to the person receiving the graft and remove the “donor” cells completely. Without any foreign cells to trigger an  immune response blood vessels can be produced ahead of time for use in any patient.

The company is also working on a technique in which the cell-produced sheets are processed into particles instead of threads. Molding the particles together could eventually produce a liver, pancreas, or kidney.

Health or horror? Let us know what you think.

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!

High hopes for long-term hemophilia B therapy

Investigators from St Jude Children’s Research Hospital and University College London recently announced extremely encouraging preliminary results of a Phase I/II gene therapy trial in patients with hemophilia B.

Hemophilia B, is a deficiency of Factor IX (FIX), one of the proteins necessary for normal clot formation. The disease affects about 1 in 30,000 people.  Without treatment, people with hemophilia B are at risk for uncontrolled, disabling and potentially fatal episodes of both internal and external bleeding.

The FIX gene is carried recessively on the X chromosome, and as a result the disorder, just like hemophilia A (FVIII deficiency), is almost exclusively seen in males, though it is carried by females.  Patients with severe hemophilia B, must normally inject themselves intravenously with FIX twice a week.

For such patients, gene therapy offers the enticing prospect of a near normal life, but previous studies have yielded disappointing results.

This study, presented last week at the American Society of Hematology annual meeting, was designed primarily to evaluate the toxicological safety study of low and intermediate doses. Because of the low dose used, researchers anticipated that trial subjects would produce little or no detectable FIX. So it was something of a positive surprise when the first patients FIX levels rose from <1% to 2% of normal, after infusion of the experimental vector.

While this rise, may not sound all that impressive, for a person with hemophilia it means the difference between severe and moderate disease.

Even more surprisingly, the patient’s FIX production remains elevated more than nine months later. Since the infusion the patient has also not suffered any spontaneous joint bleeds or needed prophylactic treatment.

Work on the vector began more than 10 years ago. An adeno-associated virus (AAV) vector known as AAV8 was picked because the incidence of natural infection with AAV8 is low and, like although it targets liver cells it does not integrate into the patient’s DNA. Participants received no immune suppressing drugs prior to infusion of the experimental vector.  The results so far suggest the experimental vector does not trigger the T-cell mediated immune response seen in a previous hemophilia B gene therapy trial.

The highest dose of the novel gene-vector combination is scheduled to be infused into the fifth and sixth study participants by mid-January. Investigators will then decide whether to expand the trial to include four more adults with severe hemophilia B.

As always SRxA’s Word on Health will be watching closely and will bring you news of further developments as they are announced.

Top 10 Medical Innovations for 2011

Yes, it’s THAT time of year again.  Frenzied last minute preparation for the holidays means shopping and shopping means lists, lists and more lists.

Here’s one more list that we thought you wouldn’t mind us sharing. It comes from The Cleveland Clinic, one of the most respected healthcare institutions in the country, who recently released its Top 10 medical innovations for 2011.  The list includes groundbreaking drugs for cancer, hepatitis and multiple sclerosis, as well as technical innovations including incision-less bariatric surgery and pill sized cameras.

To be in the running for the Top 10 list, innovations had to meet the following criteria:

• Have significant potential for short-term clinical impact (either a major improvement in patient benefit or an improved function that enhances healthcare delivery).
• Have a high probability of success
• Be on the market or close to being introduced
• Have sufficient data available to support its nomination.

So who made the list you ask?

With bated breath, a large drum roll and an annoying pause for a commercial break, here, in reverse order, dear Word on Health readers, are the winners for 2011:

10. Capsule endoscopy for diagnosis of pediatric GI disorders: A pill-sized camera that captures 50,000 high-resolution images during its painless six- to eight-hour journey through the digestive tract, proving better than x-ray at detecting small bowel ulcerations, polyps and areas of bleeding.

9. Oral disease-modifying treatment for multiple sclerosis: Before Fingolimod was approved by the FDA this year, MS drugs had to be injected or infused on a regular basis. This oral medication effectively stops T-cells from attacking the myelin sheaths that cover nerve fibers.

8. Exhaled nitric oxide (NO) breath analysis for diagnosing asthma: A new hand-held diagnostic testing device measures a patient’s level of exhaled NO, which is a biomarker for asthma. Monitoring NO levels allows doctors to more accurately tailor treatment strategies.

7. Transoral gastroplasty, or TOGA: A new experimental weight-loss option for obese patients who want to lose weight and improve their health without undergoing major surgery. This “scar-less” procedure represents a significant improvement in minimally-invasive bariatric surgery and losses approaching 40% of excess body weight can be expected within a year.

6. Telehealth monitoring for heart failure patients: Miniature implantable monitors to measure pulmonary artery pressure daily and at-home devices to monitor weight, heart rate and blood pressure of heart failure patients allow doctors to adjust medication quickly, improving patient outcomes and quality of life, while reducing re-hospitalizations.

5. Hepatitis C protease-inhibiting drugs: Two protease inhibitors drugs awaiting FDA approval for treatment of hepatitis C work by blocking a key enzyme that viruses need to copy themselves and proliferate. In clinical trials, cure rates for the protease inhibitors are higher than current hepatitis C treatments and have fewer side effects.

4. JUPITER study and statins for healthy individuals: The JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trial pointed out for the first time that many seemingly healthy people are at higher risk for heart disease than previously thought, suggesting that statins should be prescribed even to people with low LDL (bad cholesterol), if they have high C-reactive protein levels.

3. First therapeutic cancer vaccine approved by the FDA: While not a cure for prostate cancer, Sipuleucel-T is the first cancer vaccine to receive FDA approval. Prescribed to men with advanced prostate cancer, the drug coaxes their own immune systems into attacking and removing the cancer, reducing the risk of death by 24 percent compared to placebo.

2. Anti-CTLA-4 drug (ipilimumab), a targeted T-cell antibody for metastatic melanoma: The effectiveness of ipilimumab in treating melanoma confirms the role of immunotherapy as an effective treatment. In patients with advanced stage III or IV melanoma, 23% were still alive after two years compared to 14% of patients who received standard treatment.

1. New molecular imaging biomarker for early detection of Alzheimer’s disease: Currently, positive diagnosis of Alzheimer’s is only possible upon autopsy. But a radioactive molecular imaging compound called AV-45 and a PET scan can allow doctors to “see” inside patients’ brains to detect beta-amyloid plaques, the tell-tale signature of Alzheimer’s.

“If the technology is important to Cleveland Clinic it should be important to you,” said Christopher Coburn, Executive Director, Innovations, at the Cleveland Clinic.

Would these have been your picks?  SRxA’s Word on Health would like to hear from you.

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.

The skinny on blood transfusions: a modern day miracle?

Most of us have read the biblical accounts of water being turned into wine.  Now Canadian scientists have discovered how to turn skin into blood.  This miraculous breakthrough could revolutionize cancer treatments and solve the blood donor shortage.

What is more because the blood is made from the patient’s own cells, there is no danger of either rejection or infection.

The team from McMaster University, Ontario say that the process has been so successful that treatment could be available within two years.

Dr Mick Bhatia who headed the team said “People will effectively become their own donors. We are very excited and very enthusiastic about it. There is a lot of work to be done but I would be disappointed if we were not trying it on patients by 2012.”

The research, published in Nature, is part of ongoing attempts across the world to revert adult cells back to their original stem cell form. Stem cells are “master cells” which can potentially be manipulated in a laboratory to become any other cell in the body.

Human Skin Cells

What’s unique about this process is that it misses out the “in-between” stage of turning the skin cells back to stem cells and then converting them to blood cells. Instead, the cell is reprogrammed directly by inserting a specific transcription factor – a protein that interacts with DNA to activate genes – and applying cytokines or signaling molecules.

The result – within a month the skin is converted to blood.

Leukemia patients are likely to be the first to receive transfusions of perfectly matched blood generated from their own skin. In future, laboratory manufactured blood could help to plug the gap caused by donor shortages. The technique also holds out the promise of making other kinds of cell, including neurons with the potential to treat brain diseases such as Parkinson’s and Alzheimer’s.

Skin cells from both young and old people were used in the research to prove that age of donor made no difference to the process.

Next the team plans to assess what kind of production capacity might be possible with the cells, and whether they can successfully be stored in deep freeze.

As always, SRxA’s Word on Health will be watching these developments and bringing them straight to you.

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.

A giant step for mankind?

SRxA’s Word on Health was excited to learn that the FDA has finally given the all-clear to test embryonic stem cells as a potential treatment for spinal cord injury.

Geron Corp. who has invested 15 years of research and over $150 million to develop the treatment, finally hopes to start human testing by year-end.   The stem cell therapy known as GRNOPC1 contains cells called oligodendrocyte progenitor cells. Those progenitor cells turn into oligodendrocytes, a type of cell that produces myelin, a coating that allows impulses to move along nerves. When those cells are lost due to injury, paralysis can follow. If GRNOPC1 works, the progenitor cells will produce new oligodendrocytes in the injured area of the patient’s spine, potentially allowing for new movement.

The therapy will be injected into the patient’s spine 1-2 weeks after the patients suffer an injury between their third and tenth thoracic vertebrae, or roughly the middle to upper back. The company plans to enroll 8-10 patients across the U.S.  Each patient will be studied for one year and monitored for a further 15 years. A successful outcome would lead to larger and longer studies of GRNOPC1. Later trials would include patients with less severe spinal injuries and damage to other parts of the spine

Doctors are euphoric. Professor Richard Fessler,  MD, a neurological surgeon at Northwestern University says it may be possible to completely restore a patient’s motor functions.    “It would be revolutionary. The therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year.”

While this study may come too late for many high profile campaigners, including “Superman” and a former first lady, it has the promise of being a step in the right direction.

In the words of Nancy Reagan, “Countless people suffering from many different diseases, stand to benefit from the answers stem cell research can provide. As I’ve said before, time is short and life is precious.”

Right or wrong?  Word on Health looks forward to hearing from you.