Over the past several decades, I have observed remarkable progress in our understanding of spinal cord injury (SCI), a disorder once considered so intractable that its repair was described as the Holy Grail of neurological research. As demonstrated by innovative therapies being developed throughout the world, this Grail is increasingly within our grasp. So many promising procedures are in the developmental pipeline, it is difficult to keep track of them all.
However, due to a variety of regulatory, scientific and societal barriers – the pros and cons of which are debated extensively in the SCI community – the majority of the most exciting developments are happening outside the United States. Nevertheless, this obstacle does not stop motivated Americans from traveling great distances to avail themselves of these function-enhancing therapies.
Currently, one of the most talked about therapies involves the transplantation of olfactory ensheathing cell (OECs). This procedure is carried out by Dr. Hongyun Huang, professor and chief neurosurgeon, Chaoyang Hospital, Beijing, China, who I met at the Congress of Neurological Surgery (Denver) and the Rehabilitation Institute of Michigan (RIM).
Dr. Huang acquired much his OEC expertise in the US, as he worked three years in the laboratories of Dr. Wise Young (currently of Rutgers University), a leading expert on the transplantation of OECs into SCI animal models. Taking this expertise back to China, where the bench-to-bedside, technology-transfer barriers are less insurmountable, Huang developed his human OEC-transplantation procedures.
Regenerative Olfactory Tissue:
As discussed more thoroughly on articles posted on www.healingtherapies.info, the nose contains neurons that send signals to the brain when triggered by odor molecules. The axons of these neurons are enveloped by OECs, a special type of neuronal support cell that guides the axons and supports their elongation. The bundles travel from the nose to the brain’s olfactory bulb, where they make connections with other neurons. Because olfactory tissue is exposed to the external Environment (i.e., the air we breathe), it contains cells with considerable Regeneration potential, including renewable neurons, progenitor stem cells, and OECs.
Through a relatively innocuous biopsy procedure, olfactory tissue can be obtained from the nasal cavity. It can also be retrieved from the olfactory bulb, but this requires an invasive penetration of the cranial cavity that although unsuitable for human patients has been the procedure for most of the supporting animal research.
When transplanted into the injured spinal cord, OECs theoretically promote axonal regeneration by producing insulating Myelin sheaths around growing and damaged axons, secreting growth factors, and generating structural and matrix macromolecules that lay the tracks for axonal elongation.
Keeping up with promising olfactory transplantation procedures can be difficult because research teams use varying approaches. For example, Portugal’s Dr. Carlos Lima implants whole olfactory tissue obtained from the patient back into his/her injury site (see www.healingtherapies.info) Lima believes that more than one cell type is needed to maximize regeneration, including not only OECs but also olfactory neurons and stem cells. To date, Lima has treated more than 20 patients.
In another example, an Australia team implants OECs, isolated and cultured from the patient’s nasal tissue. Several patients have been treated.
In contrast, Huang transplants OECs isolated not from the patient but from fetal olfactory bulbs. Although fetal-tissue transplantation is controversial in this country, American SCI scientists also have used fetal tissue in promising research. As would be required at any America institution, Huang’s hospital ethics committee approved his clinical trials in advance. Huang has transplanted OECs into more than 300 patients with SCI, including several Americans, and thousands are on his waiting list.
In Portuguese and Australian procedures, no immunological rejection of the transplanted tissue occurs because it is patient derived; with Huang’s procedure, fetal-tissue’s undifferentiated nature minimizes immunological rejection.
The following summarizes results recently published in the Chinese Medical Journal (Chin Med J 2003; 116(10)).
Decompression: To ensure that improvement was not merely due to surgery-associated decompression, patient MRIs had to indicate the absence of compression before surgery. In addition, the cord must have some structural continuity through the injury site, the situation for most individuals with SCI.
Patient Demographics: Huang’s study included 139 men and 32 women, of which 114 were quadriplegics and 57 paraplegics. Ages ranged from 2 to 64 (average 35) years, and the interval between injury and admission varied from 6 months to18 years.
Cell Transplantation: Olfactory-bulb OECs are grown in culture media for several weeks before transplantation. After the spinal cord has been exposed through a limited Laminectomy, 500,000 cells are injected above and below the injury site. These cells presumably migrate to the injury site. Animal studies suggest that the OECs survive better when they are not directly injected into the injury site.
Functional Assessment: Function was assessed before and 2-8 weeks after surgery using the “gold standard” ASIA (American Spinal Injury Association) Impairment scales, which include Motor-function, light-touch, and pin-prick scores.
Results: Improvement was noted for each of these scores in five age categories (<20, 21-30, 31- 40, 41- 50, and >50). Interestingly, even though it is often assumed that regenerative potential is better in the young, pin-prick improvement was greatest for the 50+ category.
Patients are often regaining some sensory and motor function soon after surgery. The study design specifically eliminated spinal-cord decompression as a possible cause for this rapid functional improvement. Improvement is also too fast to be caused by neuronal regeneration or axonal remyelination.
Huang speculates that OECs wakeup quiescent neurons that still transverse the injury site, perhaps by altering the injury site’s environment through secreting growth factors and producing adhesion and matrix molecules.
Young notes that most neurons actually survive after injury, but their axons have been disconnected. He hypothesizes that by secreting a variety of growth factors, OECs may make the spinal cord more plastic or adaptable; this, in turn, encourages local axons to shift their connections.
To date, Huang has treated four Americans, including Bob, who I met during my visit to RIM. Bob, 46, sustained a C5 injury from diving into the shallow water of Michigan’s Lake St. Clair on July 4, 1999.
Bob’s improvement came quickly, including wiggling his toes hours after surgery. Three weeks after returning home, he reported a variety of additional motor and sensory improvements. For example, bowel and bladder function had improved. Specifically, Bob needs to empty his bladder less frequently because it empties more fully.
Due to improved trunk control, Bob notes that he is now able to “sit on the side of the bed for at least an hour going from side to side with little effort and shift from lying back on elbows to a sitting position by turning to either side and getting up.”
Bob’s triceps grew stronger, and his fingers gained better control. “Everything is much easier to grab,” he says. “I used a pair of scissors today cutting a wrapper off a Twizzler.” He scratches with his fingers instead of his thumbs. “I can even reach behind my head and neck to scratch my scar itch.”
Three months after surgery, Bob reports continued improvement, especially in his hands. He also notes “my upper first then lower abs have recently made an appearance.”
Although the procedure has restored significant quality-of-life-enhancing function in most patients, Huang emphasizes that OEC-transplantation is not a “cure,” and patients must keep realistic expectations. Before definitive conclusions are made, more long-term patient follow-up is needed. In addition to promising SCI results, a limited number of cases suggest that OEC transplantation may provide benefit to patients with Multiple Sclerosis, ALS (i.e., Lou Gehrig’s disease), and stroke.
A growing number of SCI scientists, including myself, who have visited China, believe this country will play a major role in the development of future SCI therapies. In China, thousands with SCI have been treated with a variety of function-restoring surgeries, none of which are currently performed in the US.
If Americans with SCI are to benefit from China’s ever-growing clinical experience, we need to proactively and open-mindedly develop bridge-building, knowledge-disseminating collaborations, including, for example, cooperative clinical trials.
(adapted from an article appearing in April 2004 “Paraplegia News”)