Chairman – Education Committee Chairman – Education Committee Indian Spinal Injuries CentreIndian Spinal Injuries Centre

Chief of Spine Service & Medical DirectorChief of Spine Service & Medical Director

International Spinal Cord Society

Korean Scientists Succeed in Stem Cell Therapy, Korea Times, 11.26.2004

In South Korea, multi-potent stem cells from umbilical cord blood were reportedly transplanted into a 37 year old woman who had not been able to stand up in 19 years due to a

gymnastics accident. Three weeks later she was apparently able to walk using a walker.

Press report – Beneficiary of Adult Stem Cell treatment for SCI & Paralysis

Testimony at Senate Committee on Science, Technology, and Space Hearing: Adult Stem Cell Research, Wednesday, July 14 2004 by Laura Dominguez

My name is Laura Dominguez. I am 19 years old and live in San Antonio, TX. Three years ago, while on the way home from summer school, my brother and I were involved in a car accident that left me paralyzed from the neck down. The accident was caused by an oil spill on the highway. An oil spill that we had nothing to do with, but by chance was on the roadway in our lane. I suffered a C6 vertebrae burst fracture and my spinal cord was severely damaged. At that time doctors gave me absolutely no chance of ever walking again. I refused to accept their prognosis and began searching for other options.After being hospitalized (in several hospitals) for almost a year, my mother and I relocated to San Diego, CA so that I could undergo extensive physical therapy. While in California, we met a family whose daughter was suffering from a similar spinal cord injury. They were also looking for

other alternatives to deal with spinal cord injuries. After extensive research and consultations with medical experts in the field of spinal cord injuries, we decided the best procedure, that exists today, was being performed in Portugal. We teamed up with the Nader family, a group of Doctors from the Detroit Medical Center, and flew to Portugal to undergo this new surgical procedure.The surgery involved the removal of tissue from my olfactory sinus area and transplanting it into my spinal cord at the injury site. Both procedures, the harvesting of the tissue and the transplant were done at the same time. I was the tenth person in the world and the second American to have this procedure done.After the surgery, I returned to California to continue physical therapy. I stayed there until July of 2003 and then returned back to San Antonio, TX. At that time an MRI was taken and it revealed my spinal cord had begun to heal. Approximately 70% of the lesion now looked like normal spinal cord tissue.I was also starting to regain feeling in my upper body and within six months I had regained feeling down to my abdomen. Improvements in my sensory feelings have continued until the present time. I can now feel down to my hip level and have started to regain feeling and some movement down to my legs. My upper body has gained more strength and balance. Another one of the most evident improvements has been my ability to stand and remain standing, using a walker, and with minimal assistance. When I stand I can contract my quadriceps and hamstring muscles. I can also stand on my toes when I am on my feet. And more importantly, while lying down in a prone position, I am able to move my feet.

My training has continued to this day and I am able to better use the muscles in my hip area. I am able, with assistance and the use of braces, to walk a distance of over 1400 feet. It takes approximately thirty minutes to walk this distance and it is extremely tiring, but it can be done. I will continue to challenge myself until I can fully walk again with little or no assistance from braces or the help of a therapist. I hope…no, I know…this will be possible by my 21st birthday.It is my understanding that the nervous system is one of the most difficult and complex to repair after an injury or trauma. But in my case, the procedure that was performed in Portugal is working as I have regained more feeling and movement. Some of the movements that I am able to make are functions that are controlled by the very tip of my spinal cord. Although the intensive physical training that I had enhanced my ability to regain strength and movement, prior to surgery I did not have the type of function and feeling that I have now.It only stands to reason that if adult stem cells can repair the complex functions of the spinal cord, they can repair and help other injured internal organs or other parts of the body, whether an injury is caused by trauma or disease. The way I see it, scientists have been given the knowledge and tools to develop and make use of adult stem cells, whether they are derived from tissue removed from the olfactory mucosa or otherwise. This knowledge should be taken full advantage of to help people overcome injuries that can be helped by stem cells or people that suffer from some terminal or debilitating diseases. At the very least, some people can benefit from the possibility of a better quality of life.

Dr ##### ####### cultivates the cells of aborted foetuses and injects them into the brains and spines of his patients. His method is controversial, but his results have led hundreds of westerners to his Beijing surgery. Jonathan Watts was given unprecedented access to the doctor and his patients

Wednesday December 1, 2004The Guardian

A clinic in China has become the focus of a medical pilgrimage for paraplegics, tetraplegics and amyotrophic lateral sclerosis sufferers from across the western

world. Doctor ##### ####### of the Xinshan hospital in Beijing is the only doctor in the world known to be pioneering a new controversial surgical procedure - using the nasal cells from aborted foetuses.

For the first time ever, Dr Huang has permitted TV cameras inside his operating theatre and this unique film records the extraordinary surgical process.

Guardianfilms now presents an extract from this report, to be broadcast tonight, December 1, at 10.30pm on BBC Newsnight. The film is distributed by Journeyman Pictures.

China's medical Mecca

A 25 year old Akbar ali, who sustained an injury to his spinal cord on the 12th of October 2006 at a construction site in Abhudabi following a fall from 12 mts, lost sensation and activity of the lower half of his body. He was treated surgically in which the bones of the vertebral column within which the spinal cord is situated were fixed using metal plates and screws after which he was on a wheel chair without any control over his bladder and bowel. The sensation and activity also didn't improve much. He arrived back in India on a wheel chair in the first week of December 2006.Incidentally when he got admitted to the #### #### Hospital, Chennai, for a reparative surgery to correct the bowel sphincter, the hospital had just got a MoU signed with NCRM for a collaborative work on stem cell based clinical applications. Immediately his case was considered for the stem cell therapy as the time elapsed from the accident until then was very short (10 weeks)

Two months after treatment, Ali was now able to walk on his own and had also regained good sensation in the legs. He did not need a catheter and could pass urine intermittently every two hours, Dr ######### said.

Crippling Spinal Cord Injuries could soon be treated at the country’s first stem cell transplant

centre

Legends

Fact !!!!!!!!!!!or

Fiction ????????

Why the confusion ?

• Understand pathophysiology

• Review cellular therapies in SCI

• Analyse the confounding variables

• Try to come to a conclusion

Why the confusion ?

• Understand pathophysiology

• Review cellular therapies in SCI

• Analyse the confounding variables

• Try to come to a conclusion

Pathophysiology of Spinal cord injury

When a tract is damaged, the cut axons produce local sprouts at the site of injury.(Ramon Y Cajal, 1928; Li & Raisman,

1995)

But even with minimal disturbance to the tract glial

framework, the sprouts did not reenter the distal part of the

tract.(Davies et al, 1996)

Pathophysiology & natural history of SCI is different ; hence management strategies & outcomes are different

Why the confusion ?

• Understand pathophysiology

• Review cellular therapies in SCI

• Analyse the confounding variables

• Try to come to a conclusion

Cell based approaches to treat spinal cord injury:

• Replacement cell therapy (Neuronal or oligodendrocyte)

• Regenerative cell therapy (Restitution of white matter long tracts)

Cell based approaches to treat spinal cord injury

• The list of experimental therapies that have been developed in animal models to improve functional outcomes after SCI is extensive

• Pre-clinical trials have shown a good potential for cellular therapies in SCI

Mackay-Sim A. Olfactory Ensheathing Cells and Spinal Cord Repair. Kieo J Med 54 (1): 8-14, March 2005.

Methods used in Replacement Cell Therapy / Stem Cell Research in SCI

• Stem cells from XenograftsPig and Murine sources

• Embryonic & Fetal stem cellsHuman fetal spinal cord

cells

• Umbilical Cord Blood stem cells

• Adult stem cells Autologous marrow stem

cells Adult neuronal stem cells

Clinical trials using Stem Cells (ESCs) From Xenografts

• Porcine Stem Cells– At Washington

University in 2001

• Embryonic Stem Cells from Blue Shark

- Dr. Fernando Ramirez (ISCRC), Tijuana, Mexico

• Results have not yet been published

Clinical trials using Human Fetal Spinal Cord (? Embryonic Stem Cells From

Fetus)

• Intraspinal transplantation– Gainesville, FL– Denver, CO– Russia

• Only safety of the procedure could be established

Clinical trials using Umbilical Cord Blood Stem Cells

• Korean researchers

• Team co-headed by Chosun University professor Song Chang-Hun

• Authenticity challenged

Adult Neural Stem Cells

• Till date no clinical trial documented

Clinical trials using Adult Marrow Stem Cells:

Source: Autologous

Route of administration: - - - intravenous or intramedullary (image guided) injection.

Prague; Korea

India - AIIMS.

• Transplantation of unmanipulated autologous bone marrow in SCI pts

• 20 pts; complete SCI; 10 to 467 days post-injury• Compared intra-arterial vs. IV• Safe; longer follow-ups required • cannot confirm beneficial effects due to cell

therapy

• 6 complete SCI pts

• BMT - injury site

GM-CSF – S/C

• Improvement

AIS A – C – 4 pts

AIS B – C – 1 pt

• Serious complications not found

• open-label, nonrandomized study • 35 complete sci pts• Injection into the surrounding area of the spinal cord injury site

– within 14 injury days = 17– between 14 days and 8 weeks = 6– more than 8 weeks after injury = 12

• No serious adverse events• Improvement - 30.4% acute and subacute pts no significant improvement - chronic pts• Long-term and large scale multicenter clinical study is required

to determine its precise therapeutic effect.

2007

Stem Cell Research

Greatest Challenge :

• To uncover the extracellular and intracellular mechanisms that determine and control the self renewal and differentiation properties of the stem cell in physiological as well as host environment

Methods used in Regenerative Cell Therapy in SCI

• Peripheral Nerve grafts

• Enriched Schwann Cells suspensions

• Activated Macrophages

• Olfactory ensheathing glial cells

• Oligodendrocyte precursor cells – preclinical stage

Peripheral Nerve Grafts

• Kao et al, 1985 (Ecuador>90 pts)

• Barros et al, 2003, Sao Palo, sural nerve graft in combination with FGF and fibrin glue

• No motor/sensory improvement; spasticity was reduced

Schwann Cell Cultures

No human trials

Activated Macrophages

• FDA approved non-randomized Phase I trial, 1999; Phase II - 2004

• Erasmus Hospital, Brussels Craig hospital, Denver

Tel Aviv

• Indicated the safety of the procedure

• Phase I, open-label nonrandomized study

• Isolating monocytes from pt blood and incubating them ex vivo with autologous dermis

• Injected into pt’s spinal cord immediately caudal to the lesion within 14 days of injury

• Three improved significantly (AIS A to C)

• well tolerated; further clinical evaluation is warranted.

Major problem in Regenerative cell therapy for SCI:

• The axon sprouts were reluctant to leave the Schwann cell environment of the transplant and reenter the glial environment of the distal CST.

(Bignami et al, 1984)

Excerpts from “Olfactory ensheathing cells and spinal cord repair”

Alan Mackay-Sim, Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Qld, Australia;

2004

• Strong candidate for Neurotransplantation therapy with the vast majority of the 53 published transplant studies reporting positive outcomes.

OEG Cells for Human SCI

• Being used in China, Portugal, Australia, India (& UK)

• Many ( > 1000 ) pts have received treatment

• Claims of success

• Administered as part of trial only at 3 Centres (one each in Australia, Portugal and India)

• Prospective clinical study involving 16 patients with chronic SCI

• Olfactory bulbs from the 3-4-month-old aborted human fetuses

• Single fetal OEC cells were then cultured for 12-17 days

• Suspension (50 microl) containing about 1 x 10(6) fetal OECs was transplanted by an injection into the patients' spinal cords

• No cell-related adverse effects

• Results indicate that our protocol is feasible and safe in treatment of patients with chronic SCI within 38 months after the injury

• 171 SCI pts

• Injected at the time of operation with OECs

• OECs transplantation can improve the neurological function of spinal cord of SCI patients regardless of their ages

• The fetal OEC transplantation can partially improve N/L function quickly in Rx of CSCI

• All the influencing factors, except the motor and light touch scores, have no impact on the functional improvement after fetal OEC transplantation

• Human pilot study• 7 ; 18 to 32 yrs , ASIA A, 6 mths to 6.5 yrs after injury• Olfactory mucosa autografts transplanted into lesions • 2 pts - return of bladder sensation• 2 - became ASIA C• Every pt - improvement in ASIA motor scores • Adverse events - mild• feasible, relatively safe, and potentially beneficial

procedure; Long-term follow up required to rule out delayed side effects and assess any further improvements.

• injury at least 2 years prior to transplantation

• Phase I design

• 3 pts ; complete, thoracic paraplegia with no implants and syrinx.

• Control group – 3 pts - no surgery

• No adverse findings till 3 years

• No significant functional or neurological changes

• feasible and safe up to 3 years post-implantation; preliminary conclusion because of the small number of trial pts.

Brain (2005)

Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trialA. Mackay-Sim et al

Brain (2008)

Autologous mucosal transplant in chronic spinal cord injury – an Indian Pilot StudyH S Chhabra et al

• Prospective Pilot Study

• 5 chronic, motor complete SCI pts with N/L level C5 - T12

• Safety and tolerability

• Efficacy assessment

- N/L, functional and psychological evaluation

- electrophysiological studies

- urodynamics

• relatively safe and feasible in AIS A participants with thoracic level injuries at 18 month follow up; no efficacy could be demonstrated which could be attributed to the procedure; it may not be possible to conclude regarding the efficacy of the procedure due to the limitations of the study

Spinal Cord, December, 2009

Autologous bone marrow transplantation in acute spinal cord injury – an Indian Pilot StudyH S Chhabra et al

• Ongoing ICMR approved Phase I/IIa Pilot Study

• Prospective Randomised single blind study

• 21 pts in 3 groups

• acute, complete SCI pts with N/L level T1 - T12

• Multicentric study in process

• “The problem is, the results are too fast for regeneration, therefore the mechanism for early recovery is not known."

Huang's former teacher, Professor Wise Young

• I don’t know how it works Dr. Huang Hongyun

• Complicating the debate is Huang's lack of statistical data and his refusal to carry out the double-blind trials …………. "This would not be legal in China," he says. "Even if it was, I wouldn't do it. Double-blind trials only harm the patient.“

Wednesday December 1, 2004, The Guardian

The Confusion

The Confusion

• Claims of success through Media about success in SCI management using Cellular Therapies

“The conventional wisdoms that he claims to have turned on their heads are that chronic spinal injuries can never be treated”

Wednesday December 1, 2004, The Guardian

• Claims not backed by proper trials

• Hardly any published reports

Why the confusion ?

• Understand pathophysiology

• Review cellular therapies in SCI

• Analyse the confounding variables

• Try to come to a conclusion

Need for Proper Clinical Trials

Factors discriminating patient outcomes (Confounding variables)

• Natural progression of SCI

• Subject bias

• Observer bias

• Plasticity of Spinal Cord

• Effects of delayed decompression

Natural progression of SCI

JW Fawcett et al: Spontaneous recovery after SCI and statistical power needed for therapeutic clinical trials; Spinal Cord; 2007

Natural progression of SCI

JW Fawcett et al: Spontaneous recovery after SCI and statistical power needed for therapeutic clinical trials; Spinal Cord; 2007

Subject bias

• Placebo effect – the effects of simply participating in a trial – subjects often show improvement, whether they are in experimental or control arm of a trial

• Placebo or sham surgery

D. Lammertse et al, Clinical Trial Design; Spinal Cord, 2007

Observer bias

• Can be overcome by blinded assessment by evaluators who are unaware of subject’s assignment to a treatment or control group

D. Lammertse et al, Clinical Trial Design; Spinal Cord, 2007

Plasticity of Spinal Cord

• Augmented physical therapy may enhance plasticity and improve some features of functional clinical end points

M.H. Tuszynski et al: Clinical trial inclusion / exclusion criteria and ethics; Spinal Cord, 2007

Effects of Delayed Decompression

• Maiman D, Larson S, Benzel E. Neurological improvement associated with late decompression of the thoracolumbar spinal cord. Neurosurg. 1984; 14: 302- 307

• Benzel EC, Larson SJ. Functional recovery after decompressive op eration for thoracic and lumbar spine fractures. Neurosurg. 19(5): 772 778; 1986.

• Transfeldt EE, White D, Bradford DS, Roche B. Delayed anterior decompression in patients with spinal cord and cauda equina injuries of the thoracolumbar spine: Spine. 1990 Sep;15(9):56

• Bradford DS, McBride GG. Surgical management of thoracolumbar spine fractures with incomplete neurologic deficits: Clin Orthop Relat Res. 1987 May;(218):201-16.

How the confusion effects patients

"This is the only place that offered us any hope," he says. "Everyone else offered only to help make me sufficient in that chair. But the chair is not my destiny. It is not ordained."

“Dr. Huang Hongyun’s willingness inspires hope - so much hope that patients are putting aside ethical qualms, paying tens of thousands of dollars and flying to Beijing to act as his guinea pigs”

Wednesday December 1, 2004, The Guardian

• Do not participate in Rehabilitation process

• Keep looking for “Cure” & do not come back to normal lifestyle

• Loose precious resources

Adverse effects of Cellular Therapies

Bohgaki et al; Autoimmun Rev. 2008 Jan;7(3):198-203. Epub 2007 Dec 3

Marx J. Cancer research. Mutant stem cell may seed cancer. Science 2003 sep 5;301(5638): 1308-1310

Tuszynski MH et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal

Cord. 2007 Mar;45(3):222-31. Epub 2006 Dec 19.

Steeves JD et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord. 2007

Mar;45(3):206-21. Epub 2006 Dec 19.

• Graft-vs-host disease (GvHD), • Graft rejection, • Bacterial infections, fungal infections and viral infections• Gastrointestinal and hepatic complications• Neurologic complications • Pulmonary complications • Increased neuropathic pain • Scar formation• Late effects after stem cell transplant

Adverse effects of Cellular Therapies

• May compromise outcomes of any future successful therapy

Bohgaki et al; Autoimmun Rev. 2008 Jan;7(3):198-203. Epub 2007 Dec 3.

Stem cell march, minus checks - Lack of research rules allows doctors to do as they like

G.S. MUDUR

Ajit Jogi and Dr Geeta Shroff at the news conference in New Delhi. Picture by Ramakant Kushwaha New Delhi, Nov. 16: Flaws in rules for medical research and a failure of government agencies to exercise their watchdog rights have facilitated controversial human embryonic stem cell studies in India, scientists have said. As reported in The Telegraph today, government officials and senior scientists have questioned claims by a Delhi-based doctor that she has used embryonic stem cell to treat nearly 100 patients with different diseases or injuries. The claims by fertility specialist Geeta Shroff, made at a news conference here today, have attracted widespread criticism from scientists who have warned that embryonic stem cell technology is not mature enough for applications in humans. Health secretary Prasanna Hota, chief guest at the conference, said his presence should not be construed as an endorsement of the work. “But sometimes, scientific knowledge cannot wait for bureaucratic apparatus,” Hota said. However, reacting to claims by Shroff, scientists have said the absence of regulatory oversight allows virtually unfettered research by the private sector in India. “It looks like anyone can do anything in medical research,” said Satish Totey, director of stem cell research at Manipal Hospital in Bangalore. “Is this the message India wants to give to the world?” One concern among scientists is that embryonic stem cell may carry the risk of tumours. Shroff has asserted that she has not broken any law. “We’re not doing anything unethical. If the ICMR tells us to stop, we will stop,” she said. Top ICMR officials said they had written to Shroff that her work did not have their approval. Existing guidelines on medical ethics make it mandatory for doctors to seek approval from the Indian Council of Medical Research for such research, but there is nothing it can do when private doctors flout guidelines. “Guidelines are only guidelines. Any violations cannot be punished,” said Dorairajan Balasubramanian, research director at the LV Prasad Eye Institute in Hyderabad, himself involved in the use of stem cell to treat eye diseases. The ICMR and the Department of Biotechnology are working to tighten stem cell research rules, but researchers believe progress has been slow. “They should have acted five years ago,” said Totey. Shroff, who got MP Ajit Jogi and other patients to talk about their experiences with her therapy at the conference, said she has informed the ICMR. But ICMR officials said Shroff had only sent details of her patients. “We don’t need patient information for approval process. We have asked for protocols ? things like patient selection criteria, the source of the embryonic stem cell, the method of injecting them and the dosage,” they said. Some stem cell researchers fear a regulatory backlash. “The rules may now become so tight that we’ll find it hard to work,” Totey said. While the ICMR has drafted legislation to make medical ethics mandatory for all, a senior official said it was hard to predict when it would come into effect. It has been cleared by the law ministry and is awaiting cabinet approval,” said Vasantha Muthuswamy, the head of basic medical sciences at the ICMR.

International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP)

Member Organizations:

ICMR Guidelines for Clinical Research

Cellular Therapies in Human SCI

Facts• The list of experimental therapies that have been developed in animal

models to improve functional outcomes after SCI is extensive

• Though pre-clinical trials have shown a good potential for cellular therapies in SCI there is no documentary proof as of now that any form of cellular therapy definitely improves outcome in management of human SCI; the adverse effects of many such therapies are well documented

• There is a need to conduct proper clinical trials; some early stage SCI clinical trials have recently been done and some have been started

• However some experimental therapies have been introduced into clinical practice without a clinical trial being completed

• Undue hype by the media and claims by professionals have a profound psychological effect on the spinal cord injured and interferes in their rehabilitation

Cellular Therapies in Human SCI

Fiction

“A Cure for Spinal Cord Injuries has been found !!!!!”

Cellular Therapies in Human SCI

Future holds a good promise

While it is important for the patients to know this, it is equally important for them to realise that their wait for a “cure” in the future should not compromise their coming back to a normal life style from the wheelchair in the present

Cellular Therapies in Human SCI

Future holds a good promise

Leaves a lot of scope for scientists & professionals to try to achieve a clinical breakthrough in this field and find a cure for this most devastating ailment that can afflict mankind

Medical DirectorMedical Director

Indian Spinal Injuries CentreIndian Spinal Injuries Centre

Chief of Spine Service &Chief of Spine Service &