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Thread: Autologous olfactory ensheathing cell transplantation in human paraplegia:

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    Autologous olfactory ensheathing cell transplantation in human paraplegia:

    Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial


    A. Mackay-Sim1, F. Féron1,2, J. Cochrane1, L. Bassingthwaighte3, C. Bayliss4, W. Davies5, P. Fronek5, C. Gray6, G. Kerr7, P. Licina8, A. Nowitzke9, C. Perry10, P.A.S. Silburn1, S. Urquhart5 and T. Geraghty5

    1National Centre for Adult Stem cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Qld 4111, Australia, 2Neurobiologie des Interactions Cellulaire et Neurophysiopathologie, CNRS UMR 6184, IFR Jean Roche, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille cedex 20, France, 3Occupational Therapy Department, Ipswich Hospital, Ipswich, Qld 4305, Australia, 4Spinal Outreach Team, 5Spinal Injuries Unit, Queensland Spinal Cord Injuries Service, Princess Alexandra Hospital, Woolloongabba, Qld 4102, 6Department of Mental Health, Gold Coast Hospital, Southport, Qld 4215, 7School of Human Movement Studies & Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Qld 4059, 8Northside Spinal Research Group, Holy Spirit Northside Hospital, Chermside, Qld 4302, 9Department of Neurosurgery and 10Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Woolloongabba, Qld 4102, Australia

    Correspondence to: Dr Alan Mackay-Sim, National Centre for Adult Stem Cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Qld 4111, Australia E-mail: a.mackay-sim@griffith.edu.au


    Summary


    Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor function below the level of injury. The trial was a Phase I/IIa design whose main aim was to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. The design included a control group who did not receive surgery, otherwise closely matched to the transplant recipient group. This group acted as a control for the assessors, who were blind to the treatment status of the patients. The control group also provided the opportunity for preliminary assessment of the efficacy of the transplantation. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumour of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. We conclude that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation, however, this conclusion should be considered preliminary because of the small number of trial patients.

    Key Words: human; transplantation; spinal cord injury; paraplegia

    Abbreviations: ASIA, American Spinal Injury Association Impairment Scale; COVS, Clinical Outcome Variables Scale; FDI, first dorsal interoseous; FIM, Functional Independence Measure; IADL, Instrumental Activities of Daily Living; MRI, Magnetic Resonance Imaging; SSEP, somatosensory evoked potentials; TMS, transcranial magnetic stimulation; ZPP, zone of partial preservation

    Received April 17, 2008. Revised July 4, 2008. Accepted July 4, 2008.



    Introduction


    Olfactory ensheathing cells are specialized glia that surround the olfactory nerve fascicles as they project from the sensory epithelium to the olfactory bulb (Doucette, 1990Go). They have generated considerable interest as candidates for cell transplantation therapies for repair of spinal cord injury after numerous preclinical studies (Raisman, 2001Go; Mackay-Sim, 2005Go; Richter and Roskams, 2007Go). They are accessible in human via biopsy through the external naris (Feron et al., 1998Go, 2005; Bianco et al., 2004Go).

    In 2002, we initiated a single-blinded, controlled trial to establish the safety and feasibility of intraspinal transplantation of autologous olfactory ensheathing cells in human spinal cord injury. An initial report described the surgical procedure and safety outcome of the trial after 1 year (Feron et al., 2005Go). This report describes in detail the design of the trial and describes the results of clinical, psychosocial, neurological and neurophysiological assessments that were made every 3/6 months over the 3 years following cell transplantation.

    In considering the design of a Phase I/IIa trial of a cell therapy in spinal cord injury, several aspects were paramount. Complete (American Spinal Injury Association Impairment Scale Grade A: ASIA A), thoracic level of injury was chosen to minimize the risk of loss of useful function above the site of injury. Choice of patients who had completed at least 6 months post injury would provide a homogeneous group with stable neurological and functional baselines from which to assess changes due to treatment. Psychosocial health and stability was considered important to counter potentially unrealistic expectations of clinical trial outcomes. It would also increase the likelihood of retaining the patients for the long follow-up period of the trial. Long-term follow-up was considered important for assessing risks associated with the development of cysts, syringomyelia or transplanted cell over-growth, or the development of neuropathic pain. Repeated assessment raised important issues of assessor variability and bias. Variability was controlled by using the same assessors throughout. Bias was controlled by having a control group of patients, with the assessors blinded to treatment group. The presence of a control group then raised the possibility of obtaining preliminary data on the therapeutic effect of cell transplantation, although this was not the primary aim of this trial.


    Methods


    Overview
    Patients were recruited after the review of medical records and personal or telephone interviews. From over 600 such interviews, 12 persons were selected who initially fitted the inclusion criteria. These people took part in the intensive selection process in which they were interviewed and educated about the nature of the trial including aims, risks and design. These people were assessed medically and radiologically and undertook the initial 2 h psychosocial assessment by psychiatrist and social worker. This assessment process selected six patients for the trial who agreed to take part as transplant recipients or as non-operated controls after being thoroughly informed of the trial and its attendant risks. The transplant recipients were counselled to expect no clinical benefit and they accepted that risk for altruistic reasons. Strict criteria were applied in order to select patients who were as homogeneous as possible within and between groups. Recruitment took place over a 2-year period so that the trial took 5 years to complete.

    After recruitment, the patients were assessed to establish baseline measures. All transplant patients then received a nasal biopsy from which olfactory ensheathing cells were grown for autologous transplantation into the injured thoracic spinal cord of the transplant recipient group. Regular assessments then followed for 3 years. Patients were not instructed to follow any particular exercise regime and all undertook their usual daily activities. Throughout the trial, at each assessment from the initial selection through to completion, a rehabilitation physician with extensive experience in management of people with spinal cord injury, who was not blind to group status, acted as reviewing physician. The reviewing physician conducted an independent neurological examination of each patient at each assessment session. He examined each patient to monitor their health with the responsibility to immediately notify the trial manager and ethics committees of any adverse events, with the power to stop the trial.

    The study was designed to maximize statistical power through the selection of homogeneous patients groups, a within subjects comparison (i.e. before and after), a non-transplanted control group, a single blind assessment regime, the same assessors throughout and a rigorous and long-term follow-up.

    The trial was approved by the ethics committees of the Princess Alexandra Hospital, Griffith University and Queensland University of Technology, according to guidelines of the National Health and Medical Research Council of Australia. The trial was approved by the Therapeutic Goods Administration of Australia and accordingly monitored by the responsible ethics committees.

    Selection criteria
    The primary inclusion criterion was a traumatic injury of the thoracic spinal cord (T4–T10) occurring 6 months to 3 years prior to enrolment in the trial, resulting in a sustained and complete loss of sensory and motor function below the injury (ASIA Category A, ‘ASIA A’ classification). Exclusion criteria included: substance abuse, spinal vertebral instability, major concurrent medical illness (e.g. carcinoma, auto-immune disease, diabetes mellitus) and ASIA Impairment Scale category other than A. Syringomyelia was also an exclusion criterion but an exemption was made for a control patient with a stable syrinx. Patients with major and current psychiatric illness, who had significant traumatic brain injury associated with the spinal cord injury or who were otherwise considered unable to provide fully informed consent were also excluded. Additional selection was based on a 1-hour interview and psychosocial assessment performed by a social worker and psychiatrist (Fronek, 2004Go). The initial interview included an assessment of understanding of research project and risk factors, evidence of patient's ability to cope with a negative/positive result, assessment of significant other/family's attitude towards research and possible negative result and other issues raised during the interview. The purpose of the interview was to select patients with a stable social and family background, who were committed to the trial, and who accepted the low probability of a change in function as a result of the trial, as well as the remote possibility that the implant procedure may cause deterioration in neurological function. This selection was considered necessary to reduce ‘false hope’ of recovery and to provide the highest probability of compliance with the demands of the trial over the 3-year assessment period.

    Transplantation procedures
    The nasal biopsy, olfactory ensheathing cell culture and surgical procedures are fully described elsewhere (Feron et al., 2005Go). In brief, biopsies were taken from the olfactory mucosa under general anaesthesia and olfactory ensheathing cells were cultured from these biopsies for 4–10 weeks. After appropriate tests for cell sterility, they were transplanted into the injured spinal cord. A laminectomy was performed and, following a durotomy, cells were injected into the spinal cord at multiple sites throughout the damaged cord and into the proximal and distal ends of the intact cord. Transplantation and surgery were performed under microscopic control and using a purpose-designed injector device (Feron et al., 2005Go).

    Initial and repeated assessments
    All assessments were performed with the assessors blinded to the group status of the patients. Before the assessments, the surgical scar of transplant recipients was covered with a bandage and a similar bandage was applied to the controls. Patients progressed through the trial in pairs, each assessed in the same sessions. Variability was reduced by the use of the same assessors throughout the study, obviating any inter-observer variability. Blinded assessors did not discuss the trial results with each other and the results of their assessments were not collated until the end of the trial. No results were revealed to patients or other trial team members during the course of the trial.

    Pre-operatively, the transplant recipients were assessed for haematology, blood chemistry and urine microbiology and screening for HIV and Hepatitis B and C status. They also received chest and thoracic spine X-rays. They were examined by the otorhinolaryngologist before olfactory tissue biopsy (Feron et al., 1998Go). All patients had their sense of smell tested on admission to the trial and 3 months later using a quantitative olfactory test (Mackay-Sim et al., 2004Go).

    Magnetic resonance imaging (MRI) undertaken on a 1.5 Tesla instrument by the Radiology Department, Princess Alexandra Hospital. MRI (T1-weighted with gadolinium and T2-weighted) was performed after selection for inclusion into the trial and at 6 months, 1, 2 and 3 years.

    The health of the patients was monitored by the reviewing spinal injuries physician and a clinical nurse. The clinical nurse took regular physical observations (blood pressure, temperature, pulse respiration rate). The spinal injuries physician undertook a physical examination, assessed anterior ASIA sensory level of impairment, skin and bowel and bladder function. Health assessments were made every 3 months.

    Mental health was assessed by a psychiatrist and social worker as part of the initial selection process and at each assessment point throughout the trial (Fronek, 2004Go). The psychiatrist made a clinical assessment of mental health status. The social worker took a social history and history of injury that included: the rehabilitation process, the adjustment to disability, current social/legal/financial situation, current care needs and services, pain and alcohol/drug use. Psychosocial assessments were made at 1 week, 1 month, 3 months, 6 months, 12 months and 3 years.

    Clinical Outcome Variables Scale (COVS) assessment was undertaken by an experienced spinal injuries physiotherapist (Campbell and Kendall, 2003Go). COVS was performed by each patient using standard instructions. If the patient felt unable to perform a skill, a score of 1 was recorded. A video was taken of each test completed by the patient. A second examiner was employed to validate the scoring. No patient was able to perform any of the ambulation items hence all these items were scored as 1. The physiotherapist also performed: respiratory function tests (spirometry) in both supine and sitting positions; an assessment of muscle tone and spasm using the Modified Ashworth Scale; a skin examination and recording of bowel and bladder self-reports; and ASIA classification of neurological function. Pain was assessed via interview using an in-house multidisciplinary pain-assessment tool that includes asking the patient to identify painful areas on the body identified on a body chart, to describe the pain using standard descriptors (burning, throbbing, sharp etc), and to identify temporal aspects of pain. Patients rated pain ‘now’, ‘at its worst’ and ‘average level’ and rated severity on a 10-point numerical rating scale as recommended (Bryce et al., 2007Go).

    An experienced spinal injuries occupational therapist undertook the Functional Independence Measure (FIM), a battery of hand function assessments, and Lawton's Instrumental Activities of Daily Living (IADL) (Lawton and Brody, 1969Go). The FIM and IADL were completed via interview/report rather than direct observation of skills. These assessments were made every 3 months.

    A neurologist undertook an examination, independently of ASIA examination, that included history, pin prick, motor assessment and assessment of light touch and pin prick impairment level measured from the sternal notch anteriorly and the spinous process posteriorly. Another neurologist assessed somatosensory evoked potentials (SSEP) evoked in the sensory cortex after electrical stimulation of the sensory nerves in the legs. SSEP was the only assessment that was not performed by the same person throughout the study. Three assessors made these measurements. Neurological assessments were made every 3 months.

    A neurophysiologist performed transcranial magnetic stimulation (TMS) of the motor cortex to evoke activity in the lower limbs bilaterally (tibial anterior, vastus lateralis) using both figure of eight and circular coils. The upper limbs served as positive controls by evoking movement in the first dorsal interoseous (FDI) muscles, stimulated with a figure of eight coil. Stimulation intensity of the FDI was set at 10% greater than the resting threshold for activation. Stimulation of the lower limb muscles was performed at the same intensity as for the FDI muscles and also at 90% and 100% of stimulator output. TMS assessments were made every 6 months.



    http://brain.oxfordjournals.org/cgi/...Zv&keytype=ref
    Last edited by Bob; 12-04-2008 at 09:11 PM.

  2. #2
    Thanks for posting this.
    Good to see that such a thorough trial has taken place for this type of cell transplant. However, only 6 patients, no functional return of any significance in any of them, with only one getting some minor sensory return. Conclusion that it is safe and produced no neuropathic pain is something I suppose, but are these results enough to take it further?

  3. #3
    I heard rumors that Alan Mackay is switching to neural stem cells which are suppose to work better.

    Paolo

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    Quote Originally Posted by paolocipolla View Post
    I heard rumors that Alan Mackay is switching to neural stem cells which are suppose to work better.

    Paolo
    apple and oranges, they probably work better together.

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