Stem Cell Therapy: The Holy Grail of Medicine

Stem cell therapy is the new buzz in medical corridors with 'miracle' cures being reported everyday. Nancy Singh analyses the promises it holds for various diseases and the growing market for it.

Four-month-old Aarohi Bhatt recently created medical history for being cured of a rare heart condition believed to be untreatable. The cause of her cure—Stem Cell Therapy (SCT) using her father's blood at Frontier Lifeline Hospital, Chennai. Besides being a difficult surgery, it was for the first time in the world that SCT was successfully done on a child so young.

Stem cell therapy is said to be expensive, however, considering that the effects of treatment are long lasting, without requiring expensive repetitive treatment, this seems affordable. Frost & Sullivan estimates that the annual cost of $2,500 per patient for SCT, at the manufacturer' s level, is an average cost distributed over several years.

For large scale of production of stem cell lines, consistency is the key factor. Dr Mahendra Rao of Stem Cell Biology Unit, Gerontology Research Center, US, agrees, "Researchers must be able to repeat each other's experiments and establish a baseline set of quality controls that will be required for large scale therapy."

Corneal limbal epithelial cells

Differentiated human neurons

Spherical shaped bone marrow mononuclear cells

Human mesenchymal cells

Human embryonic stem cells

Stem cells offer promising treatment for genetic diseases such as diabetes, where they can be a plausible alternative to recombinant proteins available in the market. "The market size for diabetes is greater than Parkinson's, because in Parkinson's the latest clinical trials are not assuring, while trials for diabetes are easy because engraftment is easy," believes Alan Colman, CEO, ES Cell International, Singapore.

Spinal repair is another area with a high patient potential. In the US alone, there were over 2,00,000 patients in 2004, and the potential value for SCT is estimated to be $4 billion in a Frost & Sullivan study.

Alzheimer's disease is another area with vast unmet needs that stem cell manufacturers are targeting. Assuming a penetration rate of 50 per cent in the current patient population base in the US, Alzheimer's therapies could be worth approximately $2 billion, according to another Frost & Sullivan study.

Similarly, various forms of cancer, coronary artery disease, and heart therapies, ophthalmology, tissue engineering, organ transplantation and gene therapy all offer tremendous promise to stem cell manufacturers.

Show Me the Money!

What would attract investors and venture capitalists to SCT? "Investors are bullish on stem cell products for diseases that cannot be cured by non-cell products. Ideally, investors are interested in stem cells products that have application in curing diseases that have plenty of unmet need,like in spinal cord injury, Parkinson's disease, cardiovascular diseases, diabetes, cornea
regeneration and off late AIDS cure," says Linda F Powers, MD, Toucan Capital, a leading US investor in stem cells and regenerative medicine. She believes that since most companies are focusing more on research, they tend to ignore the 'feasibility in terms of transportation and distribution' . "Stem cell products that are less cumbersome at the point of care, are easy to handle and those that are feasible for storage attract immediate investment," she adds.

For Ophthalmology

Leading organisations using cultured stem cell transplant are LV Prasad Eye Institute (Hyderabad), Sankara Nethralaya (Chennai), AIIMS (New Delhi), and Aditya Jyot Eye Hospital (Mumbai). These institutes grow stem cells in a culture medium in the lab and transplant them to patients suffering from chemical burns and ocular diseases. LV Prasad Eye Institute is the first hospital which has met with success in using cultured stem cells to treat corneal opacity and blindness. They have passed the clinical trial stage and treated over 250 patients with a 70 per cent success rate.

Stem cells exist in various regions of the eye, throughout one's life. So far, stem cells can be found at the outer edges of the cornea (the outer clear part of the eye covering the iris and pupil), the conjunctiva (the thin, moist membranes that covers the inner surface of the eyelids and the outer surface of the eyeball), as well as the ciliary margin (the tissue that lies just behind the iris).

The purpose of corneal or limbal stem cells is to maintain a healthy eye surface and replace cells that are lost and blinked away. The stem cells of the cornea are located at the limbus (the thin area between the clear cornea and the white sclera of the eye). These limbal stem cells can be transplanted for severe eye injuries. During this outpatient procedure, some limbal stem cells are extracted from the healthy eye of the patient (autograft), or a donor's eye (allograft) or cadaver, and then transplanted to the affected eye.

In a successful transplant, limbal stem cells or corneal stem cells will produce a new healthy layer of cells in the patient's eye. The success rate varies from 25 per cent to 70 per cent, depending on the underlying condition of the affected eye.

"The decision to use an autograft or allograft depends on the patient's condition. For example, an autograft would not be possible in a patient diagnosed with aniridia, wherein both eyes would be deficient of limbal stem cells. In cases of a unilateral chemical injury, the normal other eye can be used to harvest the limbal stem cells for cultivation and can then subsequently be transplanted into the affected eye. However, in cases of bilateral chemical burns, the relative with an unaffected eye is a better choice." informs Dr Vandana Jain, Head of Department and Consultant, Cornea, Cataract and Refractive Surgeon, Aditya Jyot Hospital, Mumbai.

Opines Dr Radhika Tandon, Professor of Ophthalmology, Dr Rajendra Prasad Eye Institute of Ophthalmic Sciences, AIIMS, "For corneal transplant, India is on par with any other country in the world."

Currently, research is ongoing on retinal stem cells (stem cells of the retina), where scientists are in the process of trying to culture them in labs. In future, it may help to cure diseases like retinal dispigmentosa, a retinal degeneration for which currently there is no cure.

In another breakthrough research, an Indian institute in collaboration with Japanese Nichi-In Centre for Regenerative Medicine (NCRM) has formed a synthetic culture medium which multiplies corneal limbal stem cells. "For the first time, we have been able to culture corneal limbal stem cells without any animal protein or human amniotic membrane," informs Dr Samuel Abraham, Director, NCRM's branch in Chennai.

Winds of Doubts

South Korean researcher, Dr Hwang Woo Suk, who won world acclaim as the first scientist to clone a human embryo and extract stem cells from it, admitted to 'faking' results. This has dampened spirits after giving hope to millions, by making a 37-year-old paralysed woman, walk again. Dr Hwang and his team's production of stem cells from cloned human embryos in 2004 was considered a major step toward treating conditions like Alzheimer's disease and spinal cord injuries.

He injected stems cells isolated from umbilical cord blood into the injury area of the woman who had sustained a T-10 complete injury from a fall. Unfortunately, according to recent reports, after her a second SCT, her condition has greatly deteriorated. She is now unable to sit erect for long time. Even after undergoing another treatment, she is unable to move.

Doctors suggested she contracted an infection the second time due to either procedural aspects or bacterial contamination of the transplanted cells. As a result, the surrounding tissues have hardened.

The researcher confirmed that in 2002 and 2003, two of his researchers donated eggs and a hospital director paid about 20 other women for their eggs.

For Spinal Cord Injuries

SCT at Lifeline Multi-Speciality Hospital, Chennai enabled 25-year-old Akbar Ali who injured his spinal cord in a fall to walk normally again. When he was admitted to a hospital in Abu Dhabi, a plate was fitted to treat his spinal fracture, but this did not offer him any abilities. The accident resulted in paralysis from the waist down.

"This is the first time that Indian doctors have resorted to SCT to cure spinal cord problems and the second time in the world of literature," said Dr JS Rajkumar, Chief Surgeon, Lifeline Multi-Speciality Hospital,Chennai

Ali underwent autologous SCT in December 2006. The Lifeline Stem Cell Team aspirated 100ml of bone marrow fluid from the hip bone, isolated the stem cells, processed in NCRM, as per the technological know-how from Dr Terunuma Hiroshi of Biotherapy Institute, Tokyo, Japan and 20 ml of this concentrate was injected into his spinal fluid. Soon, he was able to walk on his own.

"This has showcased the ability of SCT to bring people with paraplegia back to normalcy in a fast and effective manner," says Dr R Ravi Kumar, Cardiologist and STC Project Co-ordinator, Lifeline Multi-Speciality Hospital, Chennai.

Lifeline Hospital is now pursuing an active bone marrow derived stem cell programme for spinal injuries and currently seven patients are undergoing this treatment.

Unanswered Questions

On the surface, the possibilities for stem cell therapy seem limitless. Can't we use stem cell technologies to replace any diseased or damaged tissue in the body? To answer this question, researchers must figure out the true potential and limitations of stem cells. Some questions currently being addressed include:

How long will a stem cell therapy last?

The reason we age is because our cells do. So will adult stem cells used for treatment age faster? As of now, scientists do not know this.

Can we ensure that SCT won't form tumours in the body?

Embryonic stem cells are naturally programmed to divide continuously and remain undifferentiated. To be used successfully in therapies, embryonic stem cells must be directed to differentiate into the desired type of tissue and ultimately stop dividing. Any undifferentiated embryonic stem cells that are placed in the body might continue to divide in an uncontrolled manner, forming tumors known as 'teratomas'.

For Cardiology & Neurology

"We still have 20 patients in waiting, but we are very choosy"

- Dr Sanjay Cherian
Director and Staff Surgeon
Frontier Lifeline,Chennai

Treatment of heart problems using stem cells was first reported in March 2005 by AIIMS in New Delhi when trials were conducted on 35 patients. There was no mortality reported and all patients were brought in at a stage where surgery was ineffective. After six months, 56 per cent of the affected (read dead muscle) area injected with these cells showed improvement. After 18 months, this went up to 64 per cent.

The Stem Cell Facility at AIIMS was established in 2005 to explore the safety, feasibility and the efficacy of autologous (from the body itself) hematopoietic and cord blood stem cell transplantation in degenerative diseases. As of now, 360 patients have undergone SCT for various diseases.

At AIIMS, presently SCT is performed at a pilot scale for many of the
degenerative diseases like dilated cardiomyopathy, myocardial infarction, dilated cardiomyopathy and acute ischaemic stroke. "Acute myocardial infarction has moved a few steps above the pilot scale studies. The main focus is mainly on adult stem cells and umbilical cord blood stem cells at our Centre," says Dr Sujata Mohanty, Assistant Professor, Stem Cell Facility, AIIMS. Currently in phase-II trials for using autologous mononuclear cells (from the body) for various heart disorders, SCT is being administered to eight patients.

The R&D department of Frontier Lifeline Hospital, Chennai is working in collaboration with Tirupati-based C Venkateswarlu Institute for SCT. The technique used to separate these mononuclear cells is 'apheresis', which helps in isolating the stem cells from the bone marrow that differentiate only into heart cells.

Though such therapies have been conducted earlier, what is different now is the number of children opting for this has swelled. Frontier Lifeline has conducted SCT on a five-year-old girl suffering cardiomyopathy. In this case, the only alternative was heart transplant, for which no heart was available.

"All patients are under six-month review and hitherto have not shown any complications, " informs Dr Sanjay Cherian of Frontier Lifeline. "We still have 20 patients in waiting but we are very choosy." The Hospital has started an active programme in SCT for heart failure which is performed as minimally invasive heart surgery.

Meanwhile, the Manipal Education and Medical Group's (MEMG) newly spun-off entity, Stempeutics, is set to begin the country's first formal, full-scale clinical trials using stem cells. "We focus on developing therapies using adult human mesenchymal stem cells to treat people with damaged heart tissue, spinal injury, ischaemic limb (with lost circulation) , to be followed by optic nerve injury," according to Dr Ramananda Nadig. COO, Stempeutics.

Stempeutics has developed patented technology of isolation and culture of mesenchymal stem cells derived from the bone marrow which supports long-term proliferations of these cells and hence do not require repeated collection of bone marrow reducing the cost and thus making therapy affordable. One batch production of mesenchymal stem cells can easily target around 150 patients at one time and hence clinical trials become easy to perform.

"Pre-clinical studies in animals and toxicity studies are over and we are now embarking on the first-of-its- kind phase-II clinical trial for acute myocardial infarction, peripheral arterial diseases, spinal cord injury and stroke soon," informs Dr Totey.

He expects that, in another year-and-a-half for trial results and regulatory approval for the treatment, these cell therapies should be available 'off the shelf' by 2008-09 across the country's tertiary hospitals. MEMG has initially invested Rs 5 crore in creating the cell culture room, cGMP lab, quality, testing and screening facilities in a portion of its Manipal Hospital campus in Bangalore.

Internationally, doctors in Germany reported the successful use of a patient's own adult stem cells from bone marrow for regenerating tissue damaged after a heart attack in July 2001. They injected the man's own bone marrow stem cells into his damaged heart muscle. Ten weeks after treatment, the damaged area of heart tissue had considerably reduced, replaced by new cells, and the function of the patient's heart had increased by 20-30 per cent. The authors note that their results demonstrate that "transplantation of human autologous adult stem cells is possible under clinical condition". The use of the patient's own adult stem cells from bone marrow or muscle to treat damage from heart attack is also in clinical trials
in France and the US.

French physicians implanted skeletal muscle stem cells back into the patient; the encouraging result after eight months' follow-up underlines the potential of this new approach using adult stem cells. Furthermore, in February 2007, surgeons at Madrid Hospital in Spain claim to be the first to have used stem cells from a patient's fat tissue — extracted through liposuction to treat the patient's heart.

The patient, a 67-year-old man, suffered from angina and damaged coronary arteries. Plastic surgeons first performed liposuction on the patient's abdomen to remove the fat and extract and purify the stem cells. Heart surgeons then injected stem cells into the heart, where doctors hoped that they will turn into additional heart muscle and blood vessels. The fat cells were chosen for the procedure because they do not need to be cultivated for three weeks before use, as do stem cells from bone marrow.

Arohi underwent stem cell therapy at Frontier Lifeline Akbar Ali (in blue) with team of experts at Lifeline Hospital

For Diabetes

"For the first time, we have been able to culture corneal limbal stem cells without any animal protein or human amniotic membrane"
- Dr Samuel Abraham
Director, NCRM, Chennai

Posterior tibial artery, anterior tibial artery and peroneal artery are the three major blood vessels supplying blood to the foot and leg. The posterior tibial artery which forms major part of the foot and the backside of the calf was totally occluded in a 68-year-old diabetic patient with limb ischemia and had been advised an amputation of the affected area, because there was no possibility of performing a bypass surgery to salvage the limb as the distal portion of the vessel was occluded. At this juncture, Chennai's Vijaya Health
Centre's vascular team after scanning publications of international journals, resorted to this treatment. Though for other kinds of diseases such treatments have been done in other institutes in India, for diabetes this has not been reported and, in that sense, it was the first time in India.

Dr Abraham explains, "In this treatment, the patient's bone marrow was tapped under general anaesthesia and 100 ml of bone marrow was aspirated. The bone marrow stem cells were isolated and suspended for injection as per cGMP protocols at NCRM." These isolated cells were then injected to the calf muscle affected portion two times in an interval of one month. From the time of the administration of the injection, the healing started very rapidly and healthy granulation started covering the previously ischemic portion of the limb and close to 40 per cent of the foot area, 20 per cent of calf area and
100 per cent of the lateral wound region were covered by skin. The remaining portion was treated with skin grafting and could successfully heal. The patient is able to use her left lower limb as much as the right side.

Incidence of diabetes is rapidly increasing in India and is likely to see more patients. "In such patients, when there is no feasibility of a revascularisation by bypass surgery, and amputation is the only option, we can say that autologous bone marrow stem cell therapy would be suitable and safe," says Dr Abraham.

In another case, bone marrow transplant has cured experimental diabetes in mice. Can it do the same in humans? National Center for Cell Sciences (NCCS), Pune is still seeking answers. "In an effort from bench to bedside, NCCS is underway to translate the research from the scientists' bench to the patients' bedside," says Dr RR Bhonde, Deputy Director, NCCS, who has already proved how bone marrow transplant cures experimental diabetes in mice by regeneration of pancreas, the results of which he presented at SCRFI.

NCCS has now initiated human experiments as a cure for diabetes. The stem cells are isolated from bone marrow that is taken from various patients after an ethical clearance. Several samples are taken and a process is initiated to standardise the expansion of stem cells and differentiate them into pancreatic or insulin producing cells. While there is some time before human clinical trials are launched, results have been encouraging from these human experiments, Bhonde adds.

Liver Failure

Lifeline is planning to use SCT for patients needing liver transplants in association with NCRM. The programme conforms to ICMR guidelines on stem cell therapy and does not involve usage of allogenic, immunogenic, animal protein or fetal materials. The biological materials injected are bacteria- and viral-free and are derived from patients' body cells and are non-reactive.

Problem Areas

If various initiatives and projects have to be sustained, then India needs to address shortage of trained manpower in SCT. "While it is easy to build great infrastructure, we have failed in building human resources. We are far behind China in this aspect," laments Dr MK Bhan, Secretary, Department of Biotechnology, Government of India,while addressing the first annual Stem Cell Research Fourm of India (SCRFI).

"In India we do not encourage innovation among young scientists. Though we have so many genetic engineers, there is inadequate focus on R&D," adds Dr Inder Verma, Professor of Molecular Biology, Salk Institute in California.

Efforts have been made to bring clinicians and basic researchers together for interaction by organising a number of clinical research workshops, extensive training programmes, brainstorming sessions, which has resulted in the formation of the SCRFI

Dr Donald W Fink, Biologist and Regulatory Review Scientist at the US FDA, believes that it would be ideal to have a single international body to overlook all regulatory aspects of drug approvals which could have one common procedure to meet the regulatory requirements and drug approval standards. We have just started learning the first chapter in SCT and it is a long way to go before we unravel the mystery, but nevertheless it may change the course of therapy as we know it.

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