Court Rules in Favor of Taxpayer Funding for Embryonic Stem Cell Research

On July 27, 2011, U.S. District Judge Royce Lamberth ruled in the government’s favor on a federal lawsuit that challenges current NIH guidelines that allow taxpayer funding of human embryonic stem cell research. The issue presented in the lawsuit was that federal funds were used to fund research that directly destroys human embryos.  In granting the Human Health and Services motion for summary judgement, Judge Lamberth dismissed all the plaintiff’s claims.

Judge Lamberth had originally ruled in favor of the plaintiffs, Dr. James Sherley and Dr. Theresa Deisher, in a preliminary injunction in August 2010. These two researchers sued on the basis that the funding of embryonic stem cell research, which destroys embryos and violates the Dickey-Wicker Amendment, will also lessen their own chances of securing funding in an increasingly competitive environment.  The preliminary injunction granted by Lamberth temporarily shut down federal funding, but an Appeals Court placed a temporary hold on the injunction in September 2010.  The Appeals Court eventually vacated the preliminary injunction in April 2010 in a 2-1 split decision.  Supplemental briefings were filed in the case in June 2010.

In Judge Lamberth’s opinion, he noted that the April split decision by the Appeals Court tied his hands in terms of ruling on the main lawsuit.

The linguistic parsing is related to the interpretation of the Dickey-Wicker amendment, a rider placed by Congress onto funding bills since 1996, which says in part that no federal taxpayer funds can be used for “research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death. . .” The specific meaning of “research in which” has been the focal point of the arguments.

This statement agrees with his original decision regarding the merits of the preliminary injunction. Still, he obviously felt constrained by the Appeals Court.

Very Small Embryonic- like Stem Cells with Maximum Regenerative Potential get Discarded during Cord Blood Banking and Bone Marrow Processing for Autologous Stem Cell Therapy

A fascinating new paper by Deepa Bhartiya and colleagues from the Stem Cell Facility at the All India Institute of Medical Sciences in New Delhi, India hits upon a crucial problem with the way we presently make bone marrow extracts for stem cell treatments. This paper is scheduled to be published in the journal Stem Cells and Development, and the “epub” version of it has hit the web.

Bone marrow contains a wide variety of cells that have a wide range regenerative abilities. For example, the most well-characterized cell in bone marrow is the hematopoietic stem cell, which makes all the blood cells that presently circulate throughout our bodies. This blood-making stem cells can sometimes go awry and divide uncontrollably and form blood-based tumors called leukemias. Another stem cell found in bone marrow is the mesenchymal stem cell, which is part of the “stroma.” Stroma is a filigree of cells and extracellular tissue that acts as a scaffold for bone marrow. Also in bone marrow are the endothelial progenitor cells or EPCs. EPCs make blood vessels and can home to damaged tissue to help them form new blood vessels during healing. There are also a host of less well-characterized cells that are found in lower numbers in bone marrow, but may have tremendous regenerative potential. For example, marrow-isolated adult multilineage-inducible (MIAMI) stem cells can reduce inflammation, make new blood vessels and reduce necrosis (cell death) in laboratory animals that have injured limbs (see Rahnemai-Azar A, et al, Cytotherapy.2011 Feb;13(2):179-92). Also multipotent adult progenitor cells (MAPCs), which can also sustain the function of damaged limbs that have been deprived of oxygen (Aranguren XL, et al. J Clin Invest. 2008;118(2):505-14), help heal skin lesions (Herdrich BJ, Lind RC, Liechty KW. Cytotherapy. 2008;10(6):543-50), and can help suppress graft-versus-host disease (Highfill SL, et al. Blood. 2009;114(3):693-701), and VSELs or Very Small Embryonic-Like Cells. VSELs have remarkable regenerative abilities in mice (Wojakowski W. J Cardiovasc Transl Res.2011;4(2):138-44), and because these cells have been found in humans, there are high hopes for their use in human regenerative medicine (Zuba-Surma EK, et al. Cytometry A.2009 Jan;75(1):4-13).

According to Bhartiya et al., bone marrow contain VSELs, but the manner in which bone marrow is prepared for stem cell treatments, the VSELs are lost. As it turns out, the very small size of these cells causes their separation from the remaining stem cell populations during isolation. This means that one of the most potent cells in bone marrow is not present when bone marrow is used in stem bone marrow-based clinical trials.

This throws an entire new light on many bone marrow-based experiments. In particular. cardiac patients who have had bone marrow transplants from their own bone marrow. Some trials are positive, but a few are negative, and there has been a great deal of work to show that manner in which the bone marrow is isolated makes a difference. Others have argued that the manner in which the bone marrow was isolated in the negative studies is exactly the same way bone marrow is isolated when it is to be used in a bone marrow transplant. However in bone marrow transplants, the blood-making stem cells is the most important cell for the success of that procedure, not the VSELs. In the case of heart treatments, it is clear that the blood-making stem cell is not the most important cell.

Adult Stem Cells May Improve Cardiac Function In Angina Patients

Injections of a heart patient’s own stem cells can significantly reduce exercise tolerance and symptoms of angina pectoris, which is crushing chest pain that heart patients suffer when their level of exertion exceeds the oxygen delivery to the heart. This new research, which was published online in Circulation Research, showed that injections of adult patients’ own CD34+ stem cells from bone marrow aided patients who did not respond to other therapeutic options.

This research was part of a phase II prospective, double-blind, randomized, controlled clinical trial that was conducted at 26 centers in the United States. This research project is part of a long-term collaboration between scientists at Northwestern University Feinberg School of Medicine and a private company, Baxter International Inc. The objective of the trial is to determine if delivery of autologous (meaning one’s own) CD34+ stem cells directly into multiple targeted sites in the heart can reduce the frequency of angina episodes in patients suffering from chronic severe refractory angina. It is possible that CD34+ stem cells might help make new blood vessels and, therefore, increase tissue perfusion.

Lead investigator Douglas W. Losordo, MD, director, Feinberg Cardiovascular Research Institute said, “Early research across multiple disease categories suggests that stem cells generated within the body in adults may have therapeutic benefit. This is the first controlled trial treating chronic myocardial ischemia (CMI) patients with their own stem cells to achieve significant reductions in angina frequency and improvement in exercise tolerance…While we need to validate these results in phase III studies before definitive conclusions can be drawn, we believe this is an important milestone in considering whether the body’s own stem cells may one day be used to treat chronic cardiovascular conditions.”

Losordo and his team mobilized and extracted stem cells from all participants, and then randomized them to one of three treatment groups: low- or high-dose cell concentrations, or placebo, and administered the regimens in 10 distinct sites in the heart tissue through a multi-point injection catheter.

Six months after treatment, patients in the low-dose treatment group reported significantly fewer episodes of angina than patients in the control group (6.8 vs. 10.9 episodes per week), and maintained lower episodes at one year after treatment (6.3 vs. 11 episodes per week). Patients in the low-dose treatment group were also able to exercise (on a treadmill) significantly longer at six months after treatment, as compared with those in the control group (139 seconds vs. 69 seconds, on average). Angina episodes and exercise tolerance rates were also improved in the high-dose treated group at six months and at one year post treatment compared to the control group.

Norbert Riedel, Ph.D., Baxter’s chief scientific officer noted, “The concept of using one’s own stem cells to treat disease is highly attractive to the medical community and this research is consistent with Baxter’s commitment to driving scientific advances that can lead to promising new treatments for critically ill patients. These results provide important insights into the potential for these cells to be used in larger scale settings, and we look forward to moving into phase III studies in the near future to hopefully substantiate these results.”

There was no evidence of complications related to the autologous stem cells. Three deaths occurred during the trial, one from procedural complications due to the inherent risks of cardiac surgery, the others unrelated to the treatment (all in the control group). There were seven myocardial infarctions (heart attacks) in seven of the control group patients, and there were three MIs each in the low-dose and high-dose patient groups.

Previous preclinical studies of autologous CD34+ stem cells have shown an increase in capillary density and improved cardiac function in models of acute and chronic myocardial ischemia. This phase II study is based on a phase I/II study, which provided early evidence of the feasibility, safety and bioactivity of these autologous stem cells in a similar setting.

University of Pennsylvania researchers turn brain cells into heart cells

Reprogramming is the process of taking and adult cell and changing its cell fate so that it becomes another type of adult cell. For the past decade, stem cells researchers have tried to reprogram the identity of all kinds of cell types. One of the most sought-after reprogramming events is the production of heart cells, since they could be used to treat patients who have had a heart attack. Researchers at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, have demonstrated the direct conversion of a non-heart cell type into a heart cell by means of RNA transfer. Since molecules called messenger RNAs contain the information for the synthesis of specific proteins, investigators were able to change a brain cell called an astrocyte (a star-shaped brain cell) and a fibroblast (a skin cell), into a heart cell, by using mRNAs.

The scientists put an excess of heart cell mRNAs into either astrocytes or fibroblasts using lipid-mediated transfection. The host cell responds to these RNAs by transdifferentiating into another cell type. These RNA molecules direct DNA in the host nucleus to change the cell’s RNA populations to that of the destination cell type (heart cell, or cardiomyocyte),and this, in turn changes the phenotype of the host cell into the destination cell. James Eberwine, PhD, the Elmer Holmes Bobst Professor of Pharmacology, who was involved with this study, said, “What’s new about this approach for heart-cell generation is that we directly converted one cell type to another using RNA, without an intermediate step.”

The method the group used in this study is called Transcriptome Induced Phenotype Remodeling, or TIPeR. This technique is distinct from the induced pluripotent stem cell (iPS) approach used by many labs in that host cells do not have to be dedifferentiated to an embryonic, pluripotent state and then redifferentiated with growth factors to the destination cell type. TIPeR is more similar to prior nuclear transfer work in which the nucleus of one cell is transferred into another cell where upon the transferred nucleus then directs the cell to change its phenotype based upon the RNAs that are made. The cardiomyocyte work follows directly from earlier work from the Eberwine lab, where neurons were converted into Astrocytes using the TIPeR process.

The team first extracted mRNA from a heart cell, and then used TIPeR to put it into host cells. Because there are now so many more heart-cell mRNAs versus astrocyte or fibroblast mRNAs, the transfected RNAs take over the indigenous RNA population. The heart-cell mRNAs are translated into heart-cell proteins in the cell cytoplasm. These heart-cell proteins then influence gene expression in the host nucleus so that heart-cell genes are turned on and heart-cell-enriched proteins are made.

To track the change from an astrocyte to heart cell, the team looked at the new cells’ RNA profile by means of single cell microarray analysis. They also assayed the cell shape; and immunological and electrical properties of the cells. While TIPeR-generated cardiomyocytes are of significant use in fundamental science it is easy to envision their potential use to screen for heart cell therapeutics. What’s more, creation of cardiomyoctes from patients would certainly permit personalized screening for efficacy of drug treatments; screening of new drugs; and potentially as a cellular therapeutic.

National Track Athlete Treated with Stem Cell Injections and PRP

A national track and field athlete who tore her plantar-plate and severely damaged cartilage in a foot joint while participating in an indoor track events was treated with PRP injections and showed improvements. PRP stands for Platelet Rich Plasma,which is blood plasma with concentrated platelets. Platelets are used by the body to repair damaged tissue, and the concentrated platelets found in PRP contain huge reservoirs of proteins like growth factors. These growth factors are vital to the initiation and acceleration of tissue repair and regeneration. These proteins that are found in PRP initiate connective tissue healing, bone regeneration, and repair, promote development of new blood vessels, and stimulate the wound healing process.

This runner, who is named DC, was encouraged to pursued a Regenexx-SD stem cell injection procedure in December, 2010. Her 6-month follow-up is shown in this email.  She is running again and training again.  Once again, an adult stem cell treatment helps improve the quality of life of an athlete.

Stem Cell Treatments used in Racehorses

Adult stem cell treatments are not just for human patients, but also for horses. Racehorses put a great deal of strain on their leg joints, and when these joints experience the wear and tear of many races and age, treatments that use each horse’s own bone marrow stem cells seem to fix them.

This link here summarizes some recent research on stem cells treatments in horses.  Not only did autologous stem cell treatments help the horses, but the rate of re-injury was significantly lower in the horses treated with stem cell protocols when compared to those treated by traditional methods.