You don’t hear so much about olfactory ensheathing glial (OEG) cells these days. These are cells that are harvested from tissue in the nose; they have self-renewing properties and have been shown in numerous animal studies, and a few human trials, to help repair the injured spinal cord. OEG cells have been used clinically in hundreds of patients, in China, and to a lesser degree, in Portugal.
Ten or 12 years ago, these cells were one of the hot potential therapies du jour; indeed, clinical use of OEG cells (like stem cells -- from your own body) captivated the imagination of the spinal cord world, including Christopher Reeve (see below), and helped set forth a land rush in medical tourism that continues today.
I’ll offer a little OEG history. But first things first: OEG cells haven’t disappeared. They have not been discredited; there a lot of unanswered questions about what they do and how clinically relevant they are, but indeed OEG are still studied around the world (not much in the U.S., though, with the exception of a handful of studies at the Miami Project). Here are three very recent papers on OEG and spinal cord repair, one from the Geoffrey Raisman lab, University College London, Spinal Repair Unit; one from China; and one from France.
From Raisman: “Transplantation of Autologous Olfactory Ensheathing Cells in Complete Human Spinal Cord Injury."
Six chronic thoracic paraplegics were enrolled; three were a control and not treated. The other three received autologous (their own) OEG transplants.
From the paper: OEG procedure was safe and two out of three treated with cells got a lot of return.
There were no adverse findings related to olfactory mucosa biopsy or transplantation of olfactory ensheathing cells at one year after surgery. There was no evidence of neurological deterioration, neuropathic pain, neuroinfection or tumorigenesis. In one cell-grafted patient an asymptomatic syringomyelia was observed. Neurological improvement was observed only in transplant recipients. The first two operated patients improved from ASIA A to ASIA C and ASIA B….The third operated patient, although remained ASIA A, showed improved motor and sensory function of the first spinal cord segments below the level of injury. Neurophysiological examinations showed improvement in spinal cord transmission and activity of lower extremity muscles in surgically treated patients but not in patients receiving only neuro-rehabilitation. CONCLUSIONS: Observations at 1 year indicate that the obtaining, culture and intraspinal transplantation of autologous olfactory ensheathing cells was safe and feasible. The significance of the neurological improvement in the transplant recipients and the extent to which the cell transplants contributed to it will require larger numbers of patients.
From China, scientists treated eight tetraplegics all considered chronic (at least six months post injury). Y. Yang lab at the Luoyang Orthopaedic-Traumatological Hospital, Luoyang, China. "Clinical Application of Olfactory Ensheathing Cells in the Treatment of Spinal Cord Injury.
From the paper:
Three months after treatment, ASIA and FIM scores had improved significantly compared with pretreatment, though by 1 year no further significant improvements in the ASIA score were seen. The return of substantial sensation and motor activity in various muscles below the injury level was observed in three patients during follow-up. In addition, bladder function was restored in two patients. There were no serious complications postoperatively or during the follow-up period....CONCLUSIONS: This study provides preliminary evidence of the safety and possible efficacy of autologous OEC transplantation.
The French paper is titled, “Potential of Olfactory Ensheathing Cells from Different Sources for Spinal Cord Repair
,” from lead investigator Nicolas Guérout, Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, Normandy. This 2013 study is bullish about OEG for treatment of spinal cord injury but is in fact a comparison of the two sources of nasal cells, either from the olfactory bulb (harder to get) or the olfactory mucosa (they like this better):
OECs can be obtained from either the olfactory bulbs (OB-OECs) or from olfactory mucosa (OM-OECs), involving a less invasive approach for autotransplantation. However the vast majority of experimental transplantations have been focusing on OB-OECs although the OM represents a more accessible source of OECs. Importantly, the ability of OM-OECs in comparison to OB-OECs to induce spinal cord recovery in the same lesion paradigm has never been described. …. Our data demonstrate that transplantation of OECs obtained from OB or OM induces electrophysiological and functional recovery, reduces astrocyte reactivity and glial scar formation and improves axonal regrowth. We also show that the purification step is essential for OM-OECs while not required for OB-OECs. Altogether, our study strongly indicates that transplantation of OECs from OM represents the best benefit/risk ratio according to the safety of access of OM and the results induced by transplantations of OM-OECs. Indeed, purified OM-OECs in addition to induce recovery can integrate and survive up to 60 days into the spinal cord. Therefore, our results provide strong support for these cells as a viable therapy for SCI.
History of OEGs
In the big picture, the OEG story got its legs, so to speak, in 2000, with the publication of a paper from Spaniard Almudena Ramón-Cueto, in Madrid: “Functional Recovery of Paraplegic Rats and Motor Axon Regeneration in their Spinal Cords by Olfactory Ensheathing Glia
Ramon-Cueto saw functional and structural recovery in her animal models, including long regeneration of motor axons. From her paper:
In adult rats, olfactory ensheathing glia (OEG) transplants successfully led to functional and structural recovery after complete spinal cord transection. From 3 to 7 months post surgery, all OEG-transplanted animals recovered locomotor functions and sensorimotor reflexes. They presented voluntary hindlimb movements, they supported their body weight, and their hindlimbs responded to light skin contact and proprioceptive stimuli. In addition, relevant motor axons (corticospinal, raphespinal, and coeruleospinal) regenerated for long distances within caudal cord stumps. …. Our results with these cells could lead to new therapies for the treatment of spinal cord lesions in humans.
The part about regeneration, well, that stirred up a bit of controversy as not all labs were able to replicate her observations. The Mark Tuszynski lab at UC San Diego, the Os Steward lab at UC Irvine and the James Guest lab at the Miami Project saw no axonal regeneration.
Nonetheless, within two years of the Ramón-Cueto paper, the work went directly from her rat models to humans. One of the willing doctors was Carlos Lima, in Lisbon, Portugal. (Lima died a year ago.) Another was Hongyun Huang, working in Beijing, China. Both recruited a number of American patients, who typically paid more than $20,000 for the operations.
Lima’s treatment started with a laminectomy (open the back, take out some bone, expose the cord). He took a small biopsy from their nasal mucosa, literally chopped it in small pieces, and dropped the tissue into the lesion area, which in some cases he had removed scar and untethered sticky membranes. The buzz in this country on Internet chat boards was good, although I personally met several patients who got nothing from the operation.
Lima continued doing a number of operations before he was more or less pressured to show some legitimate data. In 2006 he finally produced a paper, a pilot study
with seven patients. He notes six of seven showed improvement in sensory and motor scores, but some got pain, one showed a decrease in sensory function. “Fairly” safe, he noted:
This pilot clinical study shows that autografts of olfactory mucosa are fairly safe and feasible and may possibly promote functional recovery in chronic, severe SCI in humans. … Two of 7 patients changed from ASIA A to ASIA C. Also, two patients reported return of sensations in the bladder; one of these patients also achieved voluntary contraction of the anal sphincter. … Adverse events included a few incidents of transient pain that were relieved with medication. In addition, there was a decrease in ASIA sensory scores in one patient in whom difficulty was encountered in surgically locating the injury site. Based on the encouraging findings in this study and lack of serious adverse events, further investigational clinical trials seem to be warranted.
Lima published again
in 2009; he reported that out of 20 chronic patients, 11 reportedly got better, and six went from ASIA A (complete, no motor, no sensory function) to ASIA C (incomplete, some motor or sensory function). It should be noted that this time the patients were involved in aggressive rehab, both before and after the surgery, which makes it harder to say for certain what the cell transplants might be doing.
Huang is an interesting story; to some he’s a heroic medical pioneer. Others see him as an opportunistic cell monger. He was trained, in part, at Wise Young’s lab at Rutgers. Later, he drummed up a great deal of his business from all the chatter at CareCure, the Internet community hosted by Young.
Huang has treated hundreds of people with spinal cord injuries, using not their own OEGs but cells from human fetuses. He claims most got better but has never published any data. Huang is out of the public eye, as China has made efforts to curb stem cell tourism abuses, but he’s still a busy cell transplanter, offering “Second Generation of Neurorestoration Therapy (SGNT), with the most comprehensive clinical strategies and the best clinical outcome, which is timely, adequate dosage, multi-routes, multi-cells, multi-courses, and combined treatment including cell therapy, neurorestorative medicine, neuro-modulation/stimulation and neurorehabilitation.”
Meanwhile, as Lima and Huang treated cash-paying patients, a group in Australia began an OEG trial long before the physicians did, but partly motivated by the media attention both Lima and Huang were getting. John Mackay and his group enrolled three patients but instead of tossing in chunks of nasal tissue, they cultured OEG cells as you would a stem cell. A 2005 publication
reported no functional recovery but Mackay made a very big point to include patients who could best sort out their emotions (and thereby reduce bias, and better assess risk.
A strong emphasis was placed on psychosocial selection criteria both for ethical reasons (e.g. not to raise ‘false hopes and expectations’) ....
The choice of participants with stable psychological status and social situation was considered vital for both ethical and practical reasons. Given the intense public interest and occasional ‘emotionality’ and controversy surrounding spinal cord injury ‘cure’ and regeneration research in addition to the experimental nature of this procedure, it was considered important that serious attempts were made to ensure that the participants were able to comprehend fully the potential benefits (or lack of benefit) and risks associated with the procedure. In other words, that the participants had the personal psychological strength to deal with any outcome or consequence of the study and strong family and social supports to assist them with that process.
Finally, let's consider the “Reeve Effect
.” That was the name of a longish but well-crafted New Yorker magazine piece in November 2003 about Reeve and his relentless advocacy for cure research. Reeve, in this setting, was the first to introduce many in the SCI world to Huang. At that time Reeve had already experienced some sensory return and had had diaphragm pacers implanted earlier in the year. He was not a candidate for OEG cells (injury too high up, no room for error.) But he was enthusiastic. From the magazine:
Reeve is even more excited by the work of Dr. Hongyun Huang, a Chinese neurosurgeon. Huang, making a leap that Reeve applauds and others condemn, has injected olfactory glial cells into the spinal cords of nearly four hundred paralyzed patients, including three Americans….
Since news of Huang’s success leaked out on Internet discussion groups, thousands of desperate patients have contacted him. Huang has set up a program that allows Americans and other non-Chinese to visit Beijing for one month, for surgery and preliminary rehabilitation. The cost is twenty thousand dollars; six thousand people, Huang says, are now on a waiting list for the program.
Bottom line on OEG: there are good reasons to learn more about these cells and to fill the gaps in our knowledge. For a very good overview, check out "A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury,
” which has a section on olfactory cells.
From the report (from a team of Canadians): On the plus side, OEG cells demonstrate good integration into host spinal cord; claims of axonal sprouting/regeneration have been reported.
"Behavioral improvements have been frequently reported, albeit after partial or full transection SCI models. Improvements may be due to some axonal regeneration, although trophic effects on host spinal cord likely play a role...."
On the con side:
"No robust behavioral benefits after transplantation into moderate or severe thoracic contusion injuries....Efficacy in a chronic injury model is currently lacking, and is particularly important given that this cell transplantation strategy has been forwarded into human patients with chronic SCI."