Oligodendrocyte Progenitor Cells: A Missed Opportunity

Dear Editor,

L ate last year we reviewed the potential for oligodendrocyte progenitor cells (OPCs) to successfully treat spinal cord injury (SCI), focusing in particular on the first clinical trial testing these cells on human injury. ¹ We came to the conclusion that although pre-clinical rodent data were sound, the undetermined importance of demyelination in the pathogenesis of SCI, along with safety and ethical concerns, could prove to be stumbling blocks to the success of this trial. On November 14, 2011, Geron announced the closure of its clinical trial to future enrolment, citing “uncertain economic conditions” and stating that the company would turn its attention elsewhere. ² The five patients already enrolled and treated in the trial – with no major adverse events on last reporting ³ – will receive continuing follow-up. Undoubtedly, the economic climate is unfavorable for pioneering stem cell treatments and the reasons for the cessation of this trial are multiple and complex, including development costs, the expense of multiple treatment sites, and regulatory hurdles. Nevertheless, here we explore the damaging impact that the trial's closure will have on the field of SCI.

Despite our reservations about whether OPCs would become a successful treatment for SCI, we believe that the cessation of this trial is a setback for the field and a cause for regret. Geron's pioneering efforts to get the trial into the clinic should not be understated – the company had to overcome a great deal of bureaucracy, including completing the largest-ever investigational new drug (IND) application received by the United States Food and Drug Administration (FDA) (>22,000 pages), developing manufacturing regimes, drawing up treatment protocols, complying with regulatory concerns, and enduring a number of setbacks before the trial was eventually begun. ⁴ Progressing the trial to a late stage represents a substantial investment of both time and capital, and Geron's decision to close the program in spite of this outlay will inevitably undermine confidence in the potential of stem cell therapies.

The recently stopped trial, which was dogged by safety concerns in the pre-clinical phases, was an ideal opportunity to demonstrate the safety of human embryonic stem cell (hESC)-based treatments. One of the major safety concerns surrounding hESC -based treatments is the risk of teratoma formation and immune rejection. ¹ Although there was no evidence of such complications in subsequent pre-clinical studies, unless such treatments can be proven to be safe in human trials, they are unlikely to ever succeed clinically. Even if OPCs had no clinical effect on the course of SCI, if their safety had been validated in a clinical trial, it would have been a major breakthrough for the field and a remarkable success.

Stem cell-based treatments have great potential, not just in SCI and other neurological conditions such as multiple sclerosis, ^5,6 but also in a plethora of diseases such as diabetes, end-organ failure, and immune deficiencies. ⁷ However, we have so far been unsuccessful in harnessing this potential and producing positive clinical outcomes. Although it is true that two trials using stem cells in humans are currently underway, one using adult neural stem cells in chronic SCI, ⁸ and another using embryonic stem cell derivatives as an ophthalmic treatment, ⁹ Geron's trial was particularly high profile as the first ever to use embryonic stem cell derivatives in humans, and its cessation was therefore especially poignant.

Geron's financial results indicate a net operating loss of $37 million in 2007, jumping to $111 million in 2010. ¹⁰ Indeed, losses had been increasing year to year since 2007, a trend that appears to be reversing since the cessation of the trial, with first quarter 2012 losses $5.7 million less than those for the same period last year. ¹¹ This trial had the capacity to show the world that stem cells are safe and viable; instead, its spiralling costs and ultimate cessation have sent a message that such therapies are economically risky, commercially challenging, and susceptible to failure.

It is unfortunate that a trial with so much potential to demonstrate the safety of embryonic stem cell derivatives in the human central nervous system has instead highlighted the financial risk associated with these products.