Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety.

Int Arch Med. 2012 Feb 8;5(1):5. [Epub ahead of print]

Paz Rodriguez J, Murphy MP, Hong S, Madrigal M, March KL, Minev B, Harman RJ, Chen CS, Timmons RB, Marleau AM, Riordan NH.

ABSTRACT: Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach.

PMID: 22313603 [PubMed – as supplied by publisher]

FULL TEXT: http://www.intarchmed.com/content/pdf/1755-7682-5-5.pdf

Stem Cells in Theory and Practice

Dr. Douglas J. Herthel of Alamo Pintado Equine Medical Center in Los Olivos, California was one of the first practitioners to use stem cells, beginning in 1995. Herthel used stem cells from bone marrow to treat ligament and tendon injuries in horses. The results from these treatments were so promising that he began using stem cells to treat other various conditions as well.

The treatment has since been used to treat common equine issues such as laminitis, as well as spinal cord injuries. A dramatic example is that of a donkey who suffered a spinal cord injury as was quadriplegic. The donkey regained full function following a stem cell treatment. “It’s certainly an exciting time to be in the veterinary field,” Dr. Herthel said. “You’re talking about potential cures for things, rather than just palliation. And you’re also talking about maybe less pharmacological use.” Adair, an Irish Draught Cross horse had a very severe case of chronic forelimb laminitis, so severe in fact, that without a dramatic improvement he would have to be euthanized. Adair was treated with stem cells in early 2010, 48 hours following treatment he appeared to be in less pain and six weeks later, his hooves had grown almost halfway back.

Dr. Johnson, Adair’s owner, started using stem cells in 2001 to treat tendinitis in racehorses. “The funny thing about science or lack thereof in clinical practice is you try something for what has historically not been an easy problem to fix, and you have some limited success, and you carry on,” Dr. Johnson said. Some doctors performing stem cell treatment extract and process the cells in house, while others order stem cells from another horse. Many doctors send tissue samples to Vet-Stem Inc. or other laboratories to process the cells. Dr. Robert J. Harman, Vet-Stem’s chief executive officer, said his company has processed stem cells from fat samples for about 8,000 patients since starting in 2004. About 4,000 veterinarians have completed the Vet-Stem credentialing course on stem cells as a therapy. “Once they’ve been through the course, most people are pretty strong believers that this has a place in veterinary medicine,” Dr. Harman said.

Vet-stem treats mostly horses, as well as some dogs and cats. The treatments for horses are generally for tendon and ligament injuries, while most dogs receive treatment for arthritis. Many of the dogs treated are athletes, but some are also family pets. While this is good news for people who want to see the best treatment given to man’s best friend, others caution against getting too excited over the current stem cell therapies.

Dr. Brennen A. McKenzie of Adobe Animal Hospital in Los Altos, California believes that the evidence of efficacy is preliminary. He believes that the clinics should offer the treatment as an experimental treatment in the form of a clinical trial.

A new organization, the North American Veterinary Regenerative Medicine Association, is seeking to act as a clearinghouse of information on stem cells in veterinary medicine, said Dr. Owens, director of the UC-Davis Regenerative Medicine Laboratory and NAVRMA secretary-treasurer. Hundreds of practitioners and researchers have expressed interest in being a member of the NAVRMA, and the first meeting will be in June.

The FDA has the authority to regulate the use of stem cells in animals, as they have done in humans. However, as of yet there are no specific regulations regarding the treatment of animals with stem cells.

Rare Heart Defect Reproduced in Petri Dish, Hope for Cure

Dr. Ananya Mandal, MD

A team of researchers has created beating heart cells in the lab using skin cells of children with a rare heart defect. The team, led by Ricardo Dolmetsch of Stanford University took skin cells from children with Timothy syndrome, a rare heart condition commonly associated with autism, as well as syndactyly (webbing of fingers and toes).

The process the team underwent included reprogramming the stem cells and then developing them into cardiac cells in order to have a human model to test on, instead of mice models. “Because every cell in our body has the same genetic programming, that means we can take skin cells and reprogram them to generate stem cells, and we can take those cells to make heart cells,” said Dolmetsch.

Once the heart cells were developed, the team then used them to test several heart rhythm drugs. Unfortunately, none of the drugs initially tested corrected the heart problems associated with Timothy syndrome. However, further research and testing resulted in the discovery of the success of a cancer compound roscovitine, which is now in phase 2 clinical trials. Dolmetsch added that “The potential is really large”, Stanford has applied for patents on this technology and several drug companies have expressed interest in this research.

How Nasal Stem Cells Might Prevent Childhood Deafness

Medical News Today

Sensorineural hearing loss is a type of deafness that generally begins in childhood, a condition that results from hearing cells in the cochlea losing their function. The hearing loss that occurs can often slow the development of the child and possibly cause speech and language problems to develop.

Fortunately, Australian scientists have discovered a possible way to restore or reverse this condition. It has been shown in mice that injecting nasal stem cells into the inner ear can effectively reverse the condition during early onset hearing loss. The stem cells release signaling factors that help preserve the function of the cochlear cells.

“We are exploring the potential of stem cells to prevent or restore hearing loss in people,” said project leader Dr Sharon Oleskevich. “We are encouraged by our initial findings, because all the mice injected with stem cells showed improved hearing in comparison with those given a sham injection. Roughly half of the mice did very well indeed, although it is important to note that hearing was not completely restored to normal hearing levels.”

First Scientist to identify stem cells dies at 84

Thomas Maugh II, Washington Post

Ernest Armstrong McCulloch, 84, passed away January 20 in his hometown of Toronto. Dr. McCulloch, a medical doctor who attended the University of Toronto is best remembered as the first, along with biophysicist James E. Till, to isolate and identify a stem cell.

Their discovery was reached while both were young researchers at the Ontario Cancer Institute at Princess Margaret Hospital. The discovery came as somewhat of an accident while studying the effects of ionizing radiation on mice. The aim of their study was to attempt to learn how exposure to radiation from nuclear weapons killed and also how radiation destroyed tumors. The mice were irradiated to the point that they would die within 30 days without an infusion of undamaged bone marrow cells. Shortly after injecting the cells, Dr. McCulloch discovered nodules in the spleen. His background in bacteriology allowed him to form the hypothesis that these nodules were the source of replenishing blood cells that were keeping the mice alive. These results were published, however received very little attention. Two years later, after hundreds of hours of intensive research, McCulloch and Till published a paper proving that all three types of blood cells – red, white, and platelets were produced by a single stem cell.

This discovery was the precursor for bone marrow transplant therapy, a treatment which has been utilized for 40 years and saved countless lives. “Without their work, we would never have had bone marrow transplants,” Michael Rudnicki, scientific director of the Stem Cell Network, told the Toronto Star. “We might have muddled our way through it . . . but their work provided the theoretical underpinnings for bone marrow transplant as a therapy, which has been in the clinic now for 40 years and has saved countless lives.”

Therapeutic Effects of Intra-Arterial Delivery of Bone Marrow Stromal Cells in Traumatic Brain Injury of Rats—In Vivo Cell Tracking Study by Near-Infrared Fluorescence Imaging

Neurosurgery:
February 2012 – Volume 70 – Issue 2 – p 435–444
doi: 10.1227/NEU.0b013e318230a795
Research-Animal

Osanai, Toshiya MD, PhD*; Kuroda, Satoshi MD, PhD*; Sugiyama, Taku MD, PhD*; Kawabori, Masahito MD*; Ito, Masaki MD*; Shichinohe, Hideo MD, PhD*; Kuge, Yuji PhD‡; Houkin, Kiyohiro MD, PhD*; Tamaki, Nagara MD, PhD‡; Iwasaki, Yoshinobu MD, PhD*

Abstract

BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders.

OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats.

METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry.

RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation.

CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization.

Inhaling Stem Cells for Treating Parkinson’s

Danielyan et al. Rejuvenation Res.

Stem cells have been delivered in a variety of ways: intravenously, into the spinal canal (intrathecally), into the brain (stereotactically), into the joint (intra-articularly), and into the cardiac muscle (endocardially). Scientists from the Department of Clinical Pharmacology, University Hospital of Tübingen , Tübingen, Germany have reported today a new way of delivering stem cells: via the nose.

Previous experiments administering stem cells for the treatment of Parkinson’s were primarily aimed at injection directly into the brain using sterotactic methods. These methods are highly invasive and there is always the potential of causing injury. Additionally some groups have used intravenous administration but the washout and number of cells being stuck in the lung and liver was reported as a potential problem.

The promise of using stem cells for the treatment of Parkinson’s comes not only from the direct regenerative ability of stem cells such as mesenchymal stem cells, but also from the fact that Parkinson’s is associated with inflammatory cytokine production, which has been previously demonstrated to be inhibited by stem cell administration.

Intranasal administration of bone marrow mesenchymal stem cells was performed in rats induced to develop a Parkinson’s like disease in which the dopaminergic cells were killed by administration of the toxin 6-hydroxydopamine (6-OHDA).

In rats that received the stem cells intranasally it was possible to find stem cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10(6) MSCs applied intranasally, 24% of the stem cells could be detected for least 4.5 months in the brains of 6-OHDA rats. It appears that the stem cells administered actually could proliferate in vivo as shown by expression of proliferating cell nuclear antigen on the administered mesenchymal stem cells.

Functionally it appeared that the intranasal administration increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase apoptotic cells as detected by TUNEL. Decreases in dopamine were prevented by cellular administration. A decrease in the inflammatory cytokines TNF, IFN-g, IL-2, 2, 6, and 12 was observed to be associated with the administration of cell therapy.

It will be interesting to see if this easy to apply technique will enter clinical trials. Already clinical trials are using non-conventional means of stem cell administration, for example the topical application of stem cells for burn wounds, which is being performed by Dr. Amit Patel from the University of Utah, who we interviewed for the Cellmedicine news blog above.

Ischemic Stroke Recovery May Be Improved Using Stem Cell Therapy

At the American Heart Association’s International Stroke Conference in New Orleans, two studies suggested that stem cell therapy improves functional recovery following subacute ischemic stroke and may aid in regenerative therapy.

One hundred and twenty subacute ischemic stroke patients were treated with mononuclear bone marrow-derived stem cells. Patients ranged in age from eighteen to seventy five years old. All were treated within seven to thirty days of suffering their strokes. Each patient was assessed using the Barthel index. The results showed that seventy three percent of patients who were treated with stem cells attained a Barthel score of greater than or equal to 60, which is the measure for assisted independence. Only sixty one percent of the patients who were not treated with stem cells achieved similar scores. All patients were tumor free at one year. This study was performed by Kameshwar Prasad, M.B.B.S., M.D., from the All India Institute of Medical Sciences in New Delhi.

In a separate study from the All India Institute of Medical Sciences in New Delhi, Rohit Bhatia, M.D. examined autologous mononuclear mesenchymal stem cell therapy in forty stroke patients who were recruited for the study from three months to one year after their strokes. Patients who were treated with stem cells showed significant improvement based on the Barthel index. No adverse reactions were observed. Dr. Bhatia concluded that intravenous administration of mononuclear and mesenchymal stem cells is safe, feasible and likely facilitates behavioral recovery following stroke.

Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study

Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Abstract

BACKGROUND:
More than half of patients with multiple sclerosis have progressive disease characterised by accumulating disability. The absence of treatments for progressive multiple sclerosis represents a major unmet clinical need. On the basis of evidence that mesenchymal stem cells have a beneficial effect in acute and chronic animal models of multiple sclerosis, we aimed to assess the safety and efficacy of these cells as a potential neuroprotective treatment for secondary progressive multiple sclerosis.

METHODS:
Patients with secondary progressive multiple sclerosis involving the visual pathways (expanded disability status score 5·5-6·5) were recruited from the East Anglia and north London regions of the UK. Participants received intravenous infusion of autologous bone-marrow-derived mesenchymal stem cells in this open-label study. Our primary objective was to assess feasibility and safety; we compared adverse events from up to 20 months before treatment until up to 10 months after the infusion. As a secondary objective, we chose efficacy outcomes to assess the anterior visual pathway as a model of wider disease. Masked endpoint analyses was used for electrophysiological and selected imaging outcomes. We used piecewise linear mixed models to assess the change in gradients over time at the point of intervention. This trial is registered with ClinicalTrials.gov, number NCT00395200.

FINDINGS:
We isolated, expanded, characterised, and administered mesenchymal stem cells in ten patients. The mean dose was 1·6×10(6) cells per kg bodyweight (range 1·1-2·0). One patient developed a transient rash shortly after treatment; two patients had self-limiting bacterial infections 3-4 weeks after treatment. We did not identify any serious adverse events. We noted improvement after treatment in visual acuity (difference in monthly rates of change -0·02 logMAR units, 95% CI -0·03 to -0·01; p=0·003) and visual evoked response latency (-1·33 ms, -2·44 to -0·21; p=0·020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm(2), 0·04 to 0·22; p=0·006). We did not identify any significant effects on colour vision, visual fields, macular volume, retinal nerve fibre layer thickness, or optic nerve magnetisation transfer ratio.

INTERPRETATION:
Autologous mesenchymal stem cells were safely given to patients with secondary progressive multiple sclerosis in our study. The evidence of structural, functional, and physiological improvement after treatment in some visual endpoints is suggestive of neuroprotection.

FUNDING:
Medical Research Council, Multiple Sclerosis Society of Great Britain and Northern Ireland, Evelyn Trust, NHS National Institute for Health Research, Cambridge and UCLH Biomedical Research Centres, Wellcome Trust, Raymond and Beverly Sackler Foundation, and Sir David and Isobel Walker Trust.