We are a part of a global community in which the devastation of spinal cord injury (SCI) bows to no flag, and solutions will not be any country’s exclusive domain. Integrating the diverse pieces of the puzzle necessary to develop real-world solutions requires that we open-mindedly work in cooperation and not in competition. With such cooperation, restored function after SCI will be a coalescing reality and not just a never-ending, elusive pie-in-the-sky dream.
In this spirit of bridge-building, I recently traveled to Moscow, Russia where I became the first American scientist to check-out an innovative stem-cell program for SCI developed by the NeuroVita Clinic under the direction of Dr. Andrey Bryukhovetskiy. His work is especially important because few scientists have accumulated as much hands-on experience as he has in treating human SCI with stem cells, an approach many experts believe will play a key therapeutic role in the future.
I’m always amazed how good often emerges from the tragic. For example, the Paralyzed Veterans of America (PVA), whose programs have benefited so many with SCI over the years, was born out of World War II’s violence. Bryukhovetskiy’s promising stem-cell therapies also grew out of a desire to help paralyzed veterans, in this case, those who sustained injury in Russia’s Afghan and Chechnya military conflicts.
He is a veteran, specifically a 45-year-old retired Colonel who once directed the Russian Navy’s neurology department. Because of his long-standing empathy for paralyzed veterans, Bryukhovetskiy expressed a desire to collaborate with US veteran organizations, such as PVA, to accelerate the development of real-world SCI therapies.
Bryukhovetskiy is a charismatic leader passionately committed to his mission and patients. His work in humans is built upon a strong foundation of research using a variety of SCI animal models. Because much of his research has been published in Russian, it is not well appreciated in the world’s English-emphasizing scientific community. As seems to be the case for so many innovators regardless of country, he has often struggled to carry out his pioneering research because the vision behind it runs counter to more entrenched perceptions of what is possible after SCI.
Reflecting Hippocrates’ ancient wisdom “that natural forces within us are the true healers of disease,” Bryukhovetskiy told me that stem cells “are the medicine within us.”
In 2002, Bryukhovetskiy established NeuroVita, a state-of-the-art, private clinic that treats a variety of neurological disorders. The clinic occupies several floors in a wing of the massive N.N. Blokhin Russian Cancer Research Hospital Complex five miles southeast of downtown Moscow. Staff includes numerous physicians and Rehabilitation specialists, and has access to the expertise of nearby hospital scientists. Although to date patients have been treated under an official scientific research protocol, soon after my visit, the Russian Health Ministry authorized the use of Bryukhovetsiy’s stem-cell technology for general clinical practice.
My trip to Moscow went through ten time zones, taking several days for my luggage to catch up. Because of jet lag and Moscow’s “white nights” near the summer solstice, it was difficult to sleep at night but nodding off in the day was common. During my visit, I stayed in clinic-affiliated lodging. Although few understood English, and the Russian Cyrillic alphabet makes understanding even more challenging, I was able to get around with relative ease, e.g., take the subway to the Kremlin and Red Square, go to the market, etc.
As a reflection of our emerging global community, television showed, for example, American sitcoms and Arnold Schwarzenegger movies dubbed in Russian, as well as rock videos featuring Britney Spears, unfortunately still in English. Although I was unable to talk to waiters, American rap music was often loudly played in the background. Fortunately, Bryukhovetskiy’s assistant Maria Zhukova, a former English teacher, provided excellent translational assistance.
TRANSPLANTED CELL TYPES:
Stem cells are progenitor cells that have the potential to differentiate into a variety of cells that theoretically can treat various neurological disorders. Bryukhovetskiy has used both embryonic/fetal and adult stem cells.
Although embryonic/fetal stem cells have the greatest potential to mature into a variety of cell types, they are controversial, and it is difficult to direct their differentiation pathway.
Adult stem cells are found in many tissues, including bone marrow, which produces, for example, hematopoietic stem cells that give rise to blood cells, and nervous tissue, whose stem cells can evolve into neurons and neuronal support cells (i.e., glia). Although adult stem cells usually differentiate into the specialized cells associated with the originating tissue, when certain micro-environmental cues are provided, they can mature into cells associated with other tissue. For example, under appropriate circumstances, bone-marrow-derived stem cells have the potential to become nerve cells.
Certain drugs stimulate the bone-marrow to produce more stem cells, which then spillover into the blood, where they can be collected.
When the patient is the source of the cells (i.e., autologous), there is no immunological rejection when they are re-introduced. In contrast, embryonic/fetal cells represent different genetic material (i.e., allogeneic) and have rejection potential, although to some degree their undifferentiated nature helps minimize this risk.
Bryukhovetsiy no longer uses embryonic/fetal stem cells due to the ethical controversy surrounding their use, their rejection potential, and, most importantly, his belief that autologous, adult stem cells are more effective.
In some patients, Bryukhovetskiy has transplanted autologous olfactory ensheathing cells (OECs) using procedures developed by England’s Dr. Geoffrey Raisman. Although not technically stem cells, OECs have considerable Regeneration potential and have been the focus of much attention in the SCI research community. When OECs are transplanted into the injured spinal cord, scientists theorize that these cells promote axonal regeneration by producing insulating Myelin sheaths around both growing and damaged axons, secreting growth factors, and generating structural and matrix macromolecules that lay the tracks for axonal elongation.
Improvement was evaluated using a variety of assessment procedures, including the commonly used ASIA (American Spinal Injury Association) Impairment scale in which grade A and E represents the most and least severe injury, respectively. Although this scale is frequently used, experts emphasize it is often insensitive to small but significant Functional improvements. Bryukhovetsiy has noted this insensitivity in his research; i.e. some of his patients with very real life-enhancing improvements did not improve their ASIA grade. Other measurements included FIM (Functional Independence Measure), which assesses dysfunction in daily-living activities; various electrophysiological tests designed to assess neuronal conduction; magnetic resonance imaging (MRI); and urodynamic testing for bladder function.
1) Embryonic/Fetal Cells: In 1996, the Russian Health Ministry authorized Bryukhovetskiy to carry out limited clinical trials in SCI. In these early trials, stem cells, neurons, and glia obtained from a various tissues, including 12-week-old human fetuses, were transplanted into the spinal cord/fluid of 17 patients with SCI. Their ages ranged from 16-52 (average 30) years, and the time interval between injury and transplantation ranged from 1-20 (average 5) years. Six, ten, and one had Cervical, Thoracic, and Lumbar injuries respectively. In addition to cell transplantation, all had a variety of other procedures performed depending upon their unique injuries.
Before treatment, 14 subjects were ASIA grade A and three were grade B. After transplantation (0.5 – 3-year follow-up period), four were grade A, five grade B, and seven grade C. Fifteen had some sensory improvement, seven had Motor improvement, and 12 had improved bladder function.
2) SpheroGel & Autologous Cells: Bryukhovetskiy’s team has implanted SpheroGel (a biodegradable polymer matrix) with embedded cells in six patients who required reconstructive surgeries. In three, hematopoietic stem cells were embedded, and, in the three others, olfactory cells. At follow-up (3-8 months), two grade-A patients had improved to grade C, and one had advanced to grade B. In one patient (grade B initially), there was no improvement.
3) Intrathecal Stem-Cell Transfusion: The intrathecal transfusion of autologous hematopoietic stem cells is the procedure most currently used. In this relatively straight-forward procedure involving no surgery, the patient’s stem cells are collected without anesthesia and stored with viability until they are transfused back into the patient.
To stimulate hematopoietic stem-cell production and, in turn, cell accumulation in the blood, patients typically received eight subcutaneous injections over four days of granulocytic colony-stimulating factor, a drug also called Neupogen® or Filgrastim. On day five, the patient is hooked up to a blood separator. Over 3-4 hours, blood is drawn from a vein; processed by the separator, which isolates the stems cells; and returned through another vein.
The collected stem cells are concentrated by centrifugation and slowly frozen in liquid nitrogen (-170o centigrade) in the presence of dimethyl sulfoxide (DMSO), a cryopreservative that allows cells to be frozen with minimal damage. Care is taken to check for infections so that they will not be later introduced behind the protective blood-brain barrier during transfusion.
At the time of transfusion, the stem-cell suspension is thawed and about 5.3-million cells injected intrathecally into the subarachnoid space (i.e., into the spinal fluid) through a L3-L4 lumbar puncture using a local anesthetic. The procedure, which I observed, is quick and straightforward. The patient can repeat the transfusion in two months. Bryukhovetskiy believes multiple transfusions enhance Functional recovery.
In contrast to hematopoietic stem cells, positive results have been limited with the intrathecal transfusion of olfactory cells, previously isolated and cultured from the patient’s nasal tissue.
Although Bryukhovetskiy’s team has collected stem cells from about 120 patients, for a variety of reasons, including the presence of latent infections, only about 60 have had cells reintroduced. Of these 60, 18 have had the recommended multiple transfusions. In turn, 61% of the 18 showed some functional recovery, in some cases dramatic.
Because most patients’ transfusions were relatively recent, it is too early to assess long-term benefit. Early improvements are unlikely caused by comparatively slow neuronal Regeneration processes and are probably triggered by altering the injury site’s Environment through the secretion of growth factors and other molecules.
For more scientifically inclined readers, Bryukhovetskiy hypothesizes that the stem-cells’ regenerative effects are mediated through an important growth factor called ciliary neurotrophic factor (CNTF) and its interaction with a key transmembrane receptor called gp130. This interaction, in turn, influences cell differentiation.
Like others who are developing function-restoring therapies, Bryukhovetskiy strongly believes that improvement after treatment depends upon the patient’s commitment to aggressive physical rehabilitation designed to maximize restored function. Basically, if muscles have been disconnected from brain control for many years, it’s going to take some real work to build up nascent connections. As such, his clinic emphasizes diverse rehabilitation modalities, ranging from aggressive exercises to passive massage and acupuncture therapy.
I had the opportunity to interact with a number of NeuroVita patients. Because their treatments have been relatively recent, accrued improvements have been generally modest.
Vladimir, a 40-year old Russian living in Spain, sustained a thoracic T6 complete injury from a 2001 car accident, and started a series of stem-cell transfusions late last year. He believes that these recent transfusions, combined with extensive Physical Therapy, has resulted in additional leg movement, including the ability to walk in a swimming pool.
An articulate 19-year-old Russian living in Bulgaria, Dmitri sustained a cervical C5-6 injury in a 2000 skiing accident. He has had three transfusions since the beginning of 2005 and has noted new sensation and sweating. He had some slight headaches soon after the transfusions.
>From Dagestan, Baziat, 21, sustained a T9-11 injury when she was 19. After four transfusions, she has regained additional leg and hip function.
Alexey, 32, traveled in from the distant Kamchatka Peninsula on Russia’s far eastern Pacific side, much closer to Alaska than Moscow. He shared with me the challenges of living with a severe physical Disability in a remote, almost frontier-like area of Russia. Sustaining a T-8 gunshot injury 11 years ago, he received his first transfusion last year and was scheduled to receive his third during my visit. He has acquired more bladder and bowel function and has increased leg strength and tension.
Olga, 17, sustained a T8-9 injury seven years ago from an accident. Last year, cell-containing SpheroGel was implanted in the 4-cm gap in her spinal cord. Since then, she also has had six intrathecal transfusions. Olga indicated some increased lower-back strength and improved “inner sensation.”
A year after injury, another Olga had the 5-cm gap at her T12-injury site filled with SpheroGel embedded with regenerative cells. About a year after surgery, she suddenly started gaining some dramatic improvement, which she demonstrated to me in NeuroVita’s rehabilitation facility.
These are just the patients that I met. For those interested in further patient feedback, the clinic has developed a DVD with English subtitles that includes interviews with other NeuroVita patients.
Although by itself probably not an end-all SCI panacea, this Russian stem-cell therapy is an exceedingly important piece of the puzzle that brings us ever closer to our overall goal of restored function after injury. Hopefully, American scientists can open-mindedly establish collaborations with Bryukhovetskiy so that Americans with SCI can more readily benefit.
Although Bryukhovetskiy’s work is of paramount importance, when discussing hot scientific topics like stem-cell therapy, it is easy to lose track of the fact that it is the patient who ultimately counts, not the science. In science’s cold objective eye, the patient becomes a research subject characterized by an Impairment-scale, etc, and whose subjective opinions are often left in the dust of our quest for scientific purity.
I was grateful for the opportunity to interact with NeuroVita’s patients, appreciating their willingness to share with me not only their pain and frustration, but their hope, optimism, and belief in the future. As a somewhat jaded disability-research veteran, their spirit fueled mine.
In this clinic and others throughout the world I have visited, the face of SCI seems so similar. Often with the support of devoted parents, youthful patients with great resolve, motivation, and old-soul wisdom that belies their youth pursue their dreams of recovery unencumbered with the limited expectations of the past.
In spite of unique injuries, there seems to be a collective “soul of SCI” in these patients that transcends culture and country. Although the efforts of innovative scientists, such as Bryukhovetskiy, are invaluable, the patients are the true pioneers. They each send forth a ripple of hope that is converging into a powerful current which will inevitably wash away SCI’s imprisoning walls.
Contact Information: NeuroVita Clinic, Kashirskoye Avenue 23A, Moscow, Russia;
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(adapted from September 2005 “Paraplegia News” article)