Embryonic Stem Cell Therapy At Risk? Geron Ends Clinical Trial
Embryonic stem cell therapy took a wild twist last week, when one of the first and strongest players withdrew from an ongoing embryonic stem cell-based clinical trial. After years of aggressive research and development in embryonic stem cell technology and treatment strategies, and initiating a clinical trial for spinal cord injury with fanfare, Geron, a Menlo Park, California company, decided to end their spinal cord injury clinical trial.
Geron has been aggressively financing and pursuing embryonic stem cell research and development to develop the revolutionary therapeutic method. On November 14, 2011 Geron announced that it "will discontinue further development of its stem cell programs".
Embryonic stem cells are derived from the inner cell mass of a blastocyst. A blastocyst is the first stage of differentiation of embryo cells with the formation of the outer trophoblast layer and an inner cell mass. The embryonic stem cells derived from the inner cell mass can differentiate into any cell type of the respective organism, but for the placenta. Therefore these cells are called pluripotent, not totipotent, stem cells. When appropriate growth factors are provided to these pluripotent stem cells, they differentiate into specialized cells. By controlling the growth environment, these cells can be driven to differentiate into specific cells such as neurons or oligodendrocytes. The main function of an oligodendrocyte is to insulate axons, the long neuronal projection, of the central nervous system neurons by myelin sheath. The damaged oligodendrocytes, in instances such as spinal cord injury, exposes the axons and the stem cell therapy is expected to replace the damaged oligodendrocytes and protect the neurons.
A 1998 paper published in Science "Embryonic Stem Cell line Derived from Human Blastocysts" and partially funded by Geron Corporation is an example of the company’s long standing interest in this field. In 2005, a research group lead by Dr. Hans Keirstead at the University of California Irvine published another landmark paper in this line which formed another key basis of the trial. In this paper, they reported that a treatment using cells derived from human embryonic stem cells improved mobility in rats with spinal cord injuries, providing the first physical evidence that the therapeutic use of these cells can help restore motor skills lost from acute spinal cord tissue damage. In this study, Dr Hans Keirstead and colleagues developed a technique for differentiating human embryonic stem cells into oligodendrocyte cells. When injected into rats with spinal cord injuries, the precursor cells turned into oligodendrocytes and migrated to the injured area of the spinal cord. As the cells wrapped around damaged neurons, new myelin tissue formed, allowing electrical conduction to resume and the rats to walk again.
When Geron's clinical trial protocol was approved by the U.S. FDA in 2009, to treat spinal cord injury patients, Dr. Keirstead said "This trial was approved only after rigorous safety testing and consultation of countless experts in the field. Any benefit to the patient, even an incremental one, would be a resounding victory." At present it is unclear whether one year of treatment resulted in any substantial or incremental improvement. The reported reason for Geron’s retraction from the study is financial. As per the approved protocol, the first patient, Timothy Atchinson, a 21-year-old nursing student from Alabama, received the first shot of stem cells on October 11, 2010 at Atlanta’s Shepherd Center. Atchinson was paralyzed from the waist down in a car accident. The patient was administered about two million human embryonic stem cell-derived oligodendrocyte progenitor cells, also known as GRNOPC1. These cells were supposed to form a myelin sheath around the damaged spinal cord.
Geron was the first biotech company to test human embryonic stem cells to treat a human disease. If successful, this line of treatment strategy would have been a watershed in medical science. Though Geron had a plan to treat eight patients, before pulling the plug they have already treated four patients. According to Geron, "The Phase 1 multi-center trial was designed to assess the safety and tolerability of GRNOPC1 in patients with "complete" American Spinal Injury Association (ASIA) Impairment Scale grade A subacute thoracic (T3 - T11) spinal cord injuries." They also add that it "has been well tolerated with no serious adverse events."
Now that Geron has left the field, Advanced Cell Technology of Santa Monica, California is the only other company approved by FDA to use embryonic stem cells in clinical trials.
Another player in the area is Neuralstem Inc. Unlike Geron or Advanced Cell Technology, Neuralstem Inc uses adult stem cells. As per their website, "Neuralstem is growing regionally specific cells that are already suited to the task prescribed to them once transplanted into the central nervous system. In spinal cord indications, for instance, the company will be using human spinal cord stem cells only." They add, "Neuralstem expects its transplanted cells will survive in patients and integrate into the host tissue, creating new circuitry and expressing growth factors."
Hope is still hovering strongly over Neuralstem as one of the patients diagnosed with ALS and who could barely walk at the start of the stem cell treatment is now showing improvement. According to a recent article in The Daily Beast, "Since receiving 10 stem-cell injections last March, Harada has improved enough to complete Atlanta’s two-and-a-half mile Walk to Defeat ALS on Oct. 22." Harada was quoted, “I still have ALS, but I’m starting to see signs of hope."
We have recently published several stories on stem cell research and application. One of the stories was that a synthetic windpipe, seeded with patient's own stem cells, was successfully transplanted in a patient with tracheal cancer by physicians in Sweden. Another one was on the clinical feasibility of a stem cell-based alternative to donor blood derived red blood cells. These examples show the promise and relevance of this fast developing area of research.
What is intriguing is that only few months ago Geron announced a $25 million financing (Targeted Clinical Development Award) for the GRNOPC1 from the California Institute of Regenerative Medicine. In Geron's own words, "The funding will support the clinical development of GRNOPC1, Geron's cell therapy containing oligodendrocyte progenitor cells derived from human embryonic stem cells (hESCs), currently in a Phase 1 trial in patients with spinal cord injury." With $25 million “product-backed loan” in hand, the question now is, is there something more than money involved in their decision to end this trial. Let us hope that the genuine reason for ending the trial is either financing, European patent issue or the change of leadership at Geron.
Research in animal models have shown that stem cells can do miracles. Let us hope that exit of this work-horse will not slow down clinical trial initiatives using stem cells, whether embryonic or pluripotent stem cells.
Hans S. Keirstead, Gabriel Nistor, Giovanna Bernal, Minodora Totoiu, Frank Cloutier, Kelly Sharp, and Oswald Steward. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J. Neurosci. 2005. 25 (19): 4694–705. DOI:10.1523/JNEUROSCI.0311-05.2005. PMID 15888645.
Embryonic Stem Cell Lines Derived from Human Blastocysts. James A. Thomson, Joseph Itskovitz-Eldor, Sander S. Shapiro, Michelle A. Waknitz, Jennifer J. Swiergiel, Vivienne S. Marshall and Jeffrey M. Jones.Science. 1998:282 (5391) 1145-1147. DOI: 10.1126/science.282.5391.1145.
GRNOPC1 - hESC-Derived Glial Cells. Accessed Nov 23, 2011.
University of California, Irvine Press Release. Accessed Nov 23, 2011.
Stem Cell Treatment Improves Mobility After Spinal Cord Injury. Accessed Nov 23, 2011.