For all those who were waiting with bated breath for the first ever Human Embryonic stem cell (HESC) phase I clinical trials to begin, well there’s good news. On the 30th of July 2010, the US based Geron Corporation announced the FDA’s approval to its HESC based clinical trials in humans. The announcement comes after a year-long set-back to the proposed trials, after the company discovered during some of its tests that the rats treated with the stem cell line developed cysts. This set off a spate of further tests to ensure efficacy and safety of the therapy. After a year, the company seems to have effectively allayed fears of tumorigenicity and has obtained a green signal from the US FDA and will be beginning the first human trials of Human Embryonic stem cell therapy in the world.


We are pleased with the FDA’s decision to allow our planned clinical trial of GRNOPC1 in spinal cord injury to proceed,” said Thomas B. Okarma, Ph.D., M.D., Geron’s president and CEO. “Our goals for the application of GRNOPC1 in subacute spinal cord injury are unchanged – to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient’s injured spinal cord. Additionally, we are now formally exploring the utility of GRNOPC1 in other degenerative CNS disorders including Alzheimer’s, multiple sclerosis and Canavan disease.”1

The clinical hold was placed following results from a single preclinical animal study in which Geron observed a higher frequency of small cysts within the injury site in the spinal cord of animals injected with GRNOPC1 than had previously been noted in numerous foregoing studies. In response to those results, Geron developed new markers and assays as additional release specifications for GRNOPC1. The company completed an additional confirmatory preclinical animal study to test the new markers and assays, and subsequently submitted a request to the FDA for the clinical hold to be lifted.1

The year-long delay has been a serious set-back and I can only speculate the frustration of the many people who are anxiously awaiting the trials to begin. If the therapy manages to even partially restore function in paralyzed patients, we are talking some serious progress here. The trials are only in their first phase now, but its a giant step for mankind. We could be looking at potential therapy for debilitating diseases in the near future.

The therapy developed by Geron draws upon the work of Dr. Hans Keirstead and his team at the University of California. In a revolutionary paper published in 2005 in the Journal of Neurosciences, the authors “undertook a proof of concept experiment to determine the feasibility and efficacy of using human stem cell derivatives to promote remyelination and functional recovery in the injured adult rat spinal cord.” The authors go on to elucidate, “human embryonic stem cells (hESCs) were induced to differentiate into high-purity oligodendrocyte progenitor cells (OPCs) before transplantation. This strategy obviates the potential problems posed by the capability of embryonic stem cells to form teratomas after implantation and to differentiate in ways that are determined by environmental signals at the site of implantation, which are difficult or impossible to control. High-purity OPCs were then transplanted into spinal cord injury (SCI) sites in rats 7 d or 10 months after injury. We show that rats receiving OPCs at 7 d after injury exhibited enhanced remyelination and recovery of motor function, whereas rats that received OPCs at 10 months did not. These studies demonstrate for the first time that derivatives of hESCs have therapeutic potential for spinal cord injury and indicate that there may be a limited therapeutic window for this treatment.2

About Human Embryonic Stem Cells:

Human embryonic stem cells (hESCs) are a self‑renewing source for the scalable manufacturing of functional replacement cells for every tissue and organ in the body. The hESCs with which Geron works were derived from surplus in vitro fertilized embryos originally created as part of an in vitro fertilization (IVF) procedure. The embryos, which would otherwise have been destroyed, were donated for research by the parental donors under informed consent. The hESC line that is used to produce GRNOPC1 is the H1 line. The hESCs are immortal cells, having Telomerase enzyme allowing them to grow indefinitely in culture and further, they retain the capacity to differentiate into any one of the almost 200 different types of cells present in our bodies. The official website of Geron Corp claims that their scientists can differentiate their stem cells into almost 7 distinct types of specialized cells, each of which has a potential as a treatment for some disorder. These are listed below:

  • Neural cells to treat chronic degenerative diseases of the nervous system;
  • Cardiomyocytes for the treatment of congestive heart failure and myocardial infarction;
  • Islets for the treatment of diabetes;
  • Chondrocytes for the treatment of osteoarthritis;
  • Hepatocytes for ADME drug testing;
  • Dendritic cells cells for immunotherapy for cancer and infectious diseases; and
  • Osteoblasts for the treatment of osteoporosis and bone fractures.3

The GRNOPC1 cell line is a Oligodendrocyte progenitor cell line derived from the hESC and is supposed to heal damage caused by extensive demyelination in the case of spinal cord injuries. Oligodendrocytes are naturally occurring cells in the nervous system that have several functions. Oligodendrocytes produce myelin (insulating layers of cell membrane) that wraps around the axons of neurons to enable them to conduct electrical impulses. Myelin enables efficient conduction of nerve impulses in the same manner as insulation prevents short circuits in an electrical wire. Without myelin, many of the nerves in the brain and spinal cord cannot function properly. Oligodendrocytes also produce neurotrophic factors (biologicals that enhance neuronal survival and function) to support the maintenance of nerve cells. Oligodendrocytes are lost in spinal cord injury, resulting in myelin and neuronal loss that cause paralysis in many patients with spinal cord injuries.3

It has been observed in the animal trials that if the GRNOPC1 cell line was injected into the damaged spinal cord of a rat about seven days after the injury, the treatment significantly increased the locomotary functions of the rat and improved its weight carrying capacity. With these findings, the FDA had agreed to allow Human trials to begin. However, Geron found in a single animal study that the rats developed cysts. These were microscopic and did not seem out of the ordinary as far as spinal injuries were concerned, the FDA did not want to take any chances. The trials were stalled till Geron came up with further tests and assays to prove that the cysts did not recur. For details refer this site.

The trials will now begin this year. The website provides the following information regarding the Clinical trials to be held at 7 different medical centres:

The GRNOPC1 Clinical Program

Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have GRNOPC1 injected into the lesion sites between seven and 14 days after injury.

Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enroll subjects with complete cervical injuries and expand the trial to include patients with severe incomplete (ASIA Impairment Scale grade B or C) injuries to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.

Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.4

The beauty of this treatment is that it shows promise not only for the treatment of paralyzed patients, but also for those suffering from multiple sclerosis.  The Geron study stands out even among other stem cell trials because of the capacity for healing nerve damage. In the trials, human embryonic stem cell derived glial progenitor cells will be injected directly into lesions along a patient’s spinal cord. Animal models indicate that the glial progenitor cells should work to promote nerve growth and repair the myelin sheaths on the nerves. This ‘remyelination’ of the nerves is a critical component of healing spinal cord injury as it allows signals to be passed along the nerve.

Though the current trial is being carried out primarily for safety evaluation and only those patients who have been injured after the trials commence can be a part of the trial (as the stem cells need to be injected 7 days after the injury for best results), the trial is still a landmark step and I want to wish all the very best to the scientists, the health care professionals and of course the patients who are going to be a part of this trial.

We are all waiting to see what the results will hold for the future of medicine!

References:

  1. http://www.geron.com/media/pressview.aspx?id=1229
  2. http://www.jneurosci.org/cgi/content/full/25/19/4694
  3. http://www.geron.com/grnopc1trial/grnopc1-sec1.html
  4. www.geron.com

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