Induced Pluripotent Stem Cells Make Stem Cells to Treat MS


Many nerves inside and outside the central nervous system are insulated by a sheath rich in a protein called “myelin.” This myelin-enriched sheath greatly increases the speed at which nerve impulses travel through these nerves. You have probably experienced such fast nerve impulse conduction. Remember the last time you had your hands in water that was overly hot. First there was a very sharp pain that caused you to withdraw your hand as fast as you could, but it was followed by a dull ache that became more and more painful until it abated. This is an example of the fast-moving pain impulses that help protect our limbs from further damage and the slower moving pain impulses that convey the dull ache associated with soft tissue damage.

In some cases the myelin sheath is damaged, or, in some cases, people are born with damaged myelin sheaths. Either way, such a condition is catastrophic, and multiple sclerosis is an example of a disease that results from progressive damage to and loss of the myelin sheath. Spinal cord injuries also strip the myelin sheath from many neurons, thus decreasing the effectiveness with which nerve impulses are conducted. The loss of the myelin sheath can also, in some cases, causes the death of the nerve.

Can the myelin sheath be replaced? Almost certainly. Cells make the myelin sheath and this is a cue for regenerative medicine. Many different types of stem cells can differentiate into myelin sheath-making cells. Embryonic stem cells, for example, can be differentiated into myelin sheath-making cells. This was the basis for Geron Corporation’s clinical trial with embryonic stem cell (ESC)-derived cells that could make myelin sheaths. Myelin sheath-making cells in the central nervous system are known as “oligodendrocytes,” and “oligodendrocyte progenitor cells,” which are mercifully abbreviated OPCs, give rise to oligodendrocytes. Differentiation of ESCs into OPCs led to the Geron clinical trial. However, Geron prematurely terminated this trial, and it is unclear if these embryonic stem cell-derived OPCs can restore sensation and nerve function to spinal cord injury patients.

Oligodendrocyte-Progenitor-Cell-OPC

Other cells, however, can form OPCs, and one of these is induced pluripotent stem cells (iPSCs). Since these cells are derived from the patient’s own cells, they should be recognized by the immune system as part of the patient’s own tissue and not a foreign group of cells.

Su Wang and colleagues from Steven Goldman’s lab at the Center for Translational Neuromedicine at the University of Rochester in Rochester, NY, have made patient-specific iPSCs from which they made patient-specific OPCs. Wang and his colleagues devised a protocol to differentiate human induced pluripotent stem cells (hiPSCs) into OPCs.

In this publication, Wang and others made three hiPSC lines, from which they made human OPCs. They used a very convenient methods to isolate the OPCs – fluorescence-activated cell sorting. hiPSC OPCs differentiated very efficiently into oligodendrocytes and other cell types found in the nervous system.

Next, Wang and others used their iPSC-derived OPCs to recoat nerves of mutant mice that lack myelin sheaths. Mice that have the “shiverer” mutation lack meylin sheaths, and they shake and shiver as a result of it. When implanted with Wang and companies’ iPSC-derived OPCs, these cells recoated with nerves very efficiently. When they compared the efficiency of the iPSC-derived OPCs with that of fetal OPCs, the iPSC-derived OPCs were clearly superior. The recoating of the nerves definitely increased the survival of the siverer mice. No tumors were observed in any of the mice implanted with iPSC-derived OPCs. implanted mice.

Goldman said of this study, “This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders.” Goldman continued: “The new population of OPCs and oiligodendrocytes was dense, abundant, and complete. In fact, the re-myelination process appeared more rapid and efficient than with other cell sources.” This is significant because Goldman’s team also made OPCs from ESCs and their iPSC-derived OPCs outperformed the ESC-derived OPCs as well.

Goldman is part of a collaborative research consortium with scientists from Rochester, Syracuse, and Buffalo that wants to conduct a clinical trial that uses OPCs to treat patients with multiple sclerosis. This research group is called the Upstate MS Consortium and the early stages of this study are scheduled to begin in 2015, and it will focus on cells derived from various tissue sources. Goldman anticipates that his HiPSCs-derived OPCs will be included in this project.

FDA Negotiates with Geron to End Hold


Geron Corporation has negotiated with the Food and Drug Administration to continue their Phase I trial with their embryonic stem cell-derived cell line GRNOPC[1].  To refresh your memories, As announced previously, in one preclinical study, in a preclinical study, Geron scientists saw a higher frequency of cysts in animals treated with GRNOPC[1] cells.  These cysts formed in the injury site, do not grow (are non-proliferative), are confined to the injury site, are smaller than the injury cavity, and do not seem to cause any adverse effects in the animals.  The FDA placed a hold on Geron’s Investigational New Drug Application in response to these data.

Geron apparently made a deal with the FDA to continue preclinical studies with some “new markers and assays” as agreed upon in discussions with the FDA.  Geron also said in their news release that as a “part of the ongoing plan to advance clinical development to cervical patients, Geron had already initiated this preclinical study in an animal model of cervical injury.”  They also say that Geron hopes that the study will be re-initiated in the third quarter of 2010.

Geron hopes to use their cell line to treat spinal cord injury to the cervical (upper) portion of the spinal cord as well as the thoracic (middle) portion of the spinal cord.

I hope that Geron gets this off the ground.  They have worked very hard and if their cell line helps people with spinal cord injury, then that’s great.  However what I hope we do not see are more embryos killed so that others can experiment with their cells.  In the case of Geron’s cell line, the embryos were killed long ago.  Whining about it seems to be completely counterproductive.  However if these cells can help people, then great.

We should not be surprised that there are concerns with these treatments.  It is after all, the first of its kind.  There are bound to be glitches.

About that Hold


Geron has revealed the reason for the FDA hold on its Spinal Cord Injury Investigational New Drug application. In an August 27th press release, Geron scientists revealed that the implanted GRNOPC1 cells caused cysts in a small proportion of the animals injected with them. These cysts were not cancerous. The report calls them “non-proliferative,” which simply means that they are not growing. Additionally. the cysts are very small – microscopic in size. Finally, the cysts were confined to the region of the injury and did not adversely affect the laboratory animals.

Why the hub-hub? A recent animal study reported a greater frequency of cysts. Once again, they are non-proliferative (non-growing), restricted in location to the site of injury and do not affect the animals.

What’s going on? Cyst formation is common in spinal cord injury. Once the spinal cord is injured, inflammation ensues and this involves the invasion of the spinal cord by immune cells that mop up the dead cells and debris from the injury. Unfortunately, immune cells are sloppy eaters and they do a great deal of damage to the spinal cord. The damage they cause also tends to summon more immune cells, which come to the scene of the injury and damage the spinal cord even more. the whole thing is a positive feedback mess.

To put an end to it the spinal cord makes a plug called a glial scar. The glial scar comes from the stem cell population in the spinal cord. These stem cells form support cells called “glial cells” and these cells plug the hole in the spine and shut out the immune response, thus saving the spinal cord. The formation of this glial scar, however has a severe downside for spinal cord regeneration: the glial scar is loaded with chemicals that repel growing neurons. Therefore, those neurons that were severed by the injury could not regrow their extensions if they wanted to. The glial scar acts like a bunch of burly security guards that prevent the neuronal extensions from getting to the other side.

These cysts are probably the result of the GRNOPC1 cells forming tiny glial scars to help the injured spinal cord heal. Now they do not seem to affect the laboratory animals, but they are inhibitors of neuronal healing. Therefore, while they may not affect the laboratory animals, they may represent a fix that sentences the spinal cord to never being fixed by anything else again.

GERON’S IND FOR SPINAL CORD INJURY PLACED ON HOLD


Geron Corporation has made a cell line called GRNOPC1 from embryonic stem cells. GRNOPC1 is an “oligodendrocyte precursor cell” or OPC line. Before you blow a gasket at the sight of such a long-winded description, just remember that nerves are like wires and wires need insulation.  OPCs are the cells that make the insulation.  During spinal cord injury, the insulation dies off and it causes nerves to malfunction.

In collaboration with Hans Keirstead at UC Irvine, Geron developed a protocol for the administration of GRNOPC1 cells to animals with acute spinal cord injuries. His protocol showed that the OPCs were safe (no tumors were seen, even after one year) and somewhat effective. Some scientists were skeptical, since the mice had somewhat less severe spinal cord injuries.  Nevertheless, Geron was granted an Investigational New Drug Application from the FDA to conduct a Phase I trial with their OPC cell line.

They apparently, however, have bit a bit of a snag. Here is a press release from Geron Corporation.

Geron Corporation today announced that its IND (Investigational New Drug application) for GRNOPC1, a cell therapy for neurologically complete, subacute spinal cord injury, has been placed on clinical hold by the FDA pending the agency’s review of new nonclinical animal study data submitted by the company. A clinical hold is an order that the FDA issues to a sponsor to delay a proposed trial or to suspend an ongoing trial.

Since filing the IND, Geron has been undertaking studies to enable dose escalation of its spinal cord injury product, and has been investigating application of the product to other neurodegenerative diseases. The company has also been performing additional product characterization and conducting further animal studies. Data from this work has been submitted to the FDA. Geron will work closely with the FDA to facilitate their review of the new data and to release the clinical hold. No patients have yet been treated in this study.

From the sound of it, this hold is merely an administrative procedure that the FDA routinely undergoes when presented with new data.  However, if the new data is completely consonant with previous findings, why would there be a hold? We simply do not know at this time.  It is entirely possible that nothing is amiss, and this is merely FDA policy.  However, it is also possible that Geron’s new product does not behave exactly as they thought.

The development of the first cholesterol-lowering drug (lovastatin) experienced a slow-down when a related product being developed in Japan caused cancer in dogs. Roy Vagelos, president of Merck at the time, contacted the FDA and suspended all clinical trials. Further testing by Merck showed that this was an anomaly, and extensive clinical use has vindicated this finding. Maybe this is a similar situation for Geron’s OPC line?  Only time will tell.