Joint Preservation Blog

February 12, 2009

ISSCR Guidelines for Clinical Stem Cell Translation

Filed under: Regulation, stem cell — Tags: , , , , — D @ 1:26 am

As you may recall, the International Society of Stem Cell Researchers (ISSCR) released their new guidelines in response to many “off-shore” stem cell companies offering unknown origin “stem cells” to treat just about any illness. I was happy to see these guidelines. We think it’s important to compare the Regenexx Procedure to these guidelines. To make these easier to follow, the guidelines have been paraphrased.

  • Stem cells from other people are more risky and need to be more closely monitored. The Regenexx procedure only uses autologous mesenchymal stem cells (MSC’s). This means that the stem cells that are used are only from the same patient. Research would suggest that stem cells from a donor may carry a genetic disease transmission risk. This means that cells from the bone marrow of another patient with osteoporosis may transmit that genetic disease to another patient.
  • The use of animal components to grow cells must be replaced by human or non-animal components. Stem cells are commonly cultured in Fetal Calf Serum. With the infectious risks associated with FCS (for example, mad cow disease), FCS is not appropriate for human use. As a result, the Regenexx procedure (using a patent pending procedure) grows the patient’s stem cells in the natural growth factors obtained from the patient’s own blood platelets.
  • Adverse changes to cells during culture must be minimized. In research, stem cells are often tricked into growing for extended periods. This can cause problems to develop in the cells, which can lead to the possibility of tumor formation. Extensive medical research has shown that MSC’s can be grown for about 5-6 weeks before they show signs of problems. We take a more conservative stance, that cells should only usually be grown for a maximum of 10-20 days.
  • The level of oversight of stem cell therapy should be proportional to the risk. Stem cells from someone else’s body (allogeneic) should be scrutinized more closely than autologous (from the same person). Stem cells that are embryonic or cord blood in origin should also be considered to have more risk than adult stem cells. In addition, cells that are either heavily modified or manipulated (for example stem cells with changes to their genes) are more risky than cells that have been minimally manipulated. Finally, stem cells, which perform a certain function in the body, that are used to perform a different function in therapy (non-homologous) are more risky than homologous (stem cells that usually repair cartilage being used to repair cartilage). The Regenexx procedure takes the safest route on all of this issues-we use only autologous, adult origin, minimally manipulated, and homologous cells.
  • Cells should be handled with adherence to set industry guidelines. The Regenexx procedure lab undergoes voluntary annual or biannual audits by Reglera, a leader in the cell culture standards industry. We follow all cGTP guidelines.
  • Cell banking should have high standards. We offer patients the ability to freeze and store cells that are not being used for an active procedure. Rather than rely on the industry standard of liquid nitrogen storage, we have decided on the more expensive and higher standard of dry phase storage. Our rationale is that recent research questions whether viruses may be transmitted between patient’s samples via liquid nitrogen.
  • Successful animal models are needed before stem cell therapy can be tried in humans. The Regenexx procedure uses only successful animal models before considering a treatment trial in human patients. For example, animal data must exist on the use of MSC’s for a specific application (like cartilage or tendon repair) before we will consider adding that disease to be treated. In addition, each new application for the procedure goes through a trial test period in an IRB approved study. Clinic physicians then use 3.0T MRI, exam, and patient reporting to decide if the procedure is working before releasing that treatment for commercial patients.
  • Large animal models need to be used for tissue repair studies such as tendon, bone, or cartilage. Regenerative Sciences spent a year porting a large animal model treatment to a human model. The large animal model had proved successful before we considered moving the procedure to a human model.
  • The cell line chosen for the therapy must first be shown not to be toxic or have adverse effects in the test tube or in animal models. We chose MSC’s because as of 2009 there are more than 7,000 published articles on this cell line. MSC’s are the most extensively researched of almost any stem cell line and known in animal models (as we deploy them) not to be toxic or associated with significant adverse outcomes.
  • The risk of stem cell lines causing tumors must be accessed. We have already submitted early safety data for publication and maintain an extensive tracking database to rule out that stem cells from the Regenexx procedure are causing tumors. As of early 2009 this tracking database had 300 patients, with 600 expected by the end of 2009. No tumorogenicity has been observed.
  • Animal models should exist which allow the clinician to determine the response of the stem cells to drugs the patient may be taking. The reason we chose the MSC stem cell line was the fact that so much data has been collected in animal models. We have many papers on the effects of everything from NSAID’s to obscure drugs on MSC’s. In addition, we have extensive clinical culture experience and have developed our own database of drugs that will reduce stem cell yield. Finally, we council our patients to get off of all possible prescription and non-prescription drugs prior to the procedure.
  • All studies performed using stem cells should have a multidisciplinary review board to oversee human safety. The Regenexx procedure was developed under the auspices of a department of Health and Human Safety registered Institutional Review Board.
  • The stem cell based therapy must offer a clinical advantage over existing therapies. The Regenexx procedure offers a lower risk option over traditional surgical options, which produce more tissue trauma, more downtime, more risk for infection or surgical adverse events.
  • Patient monitoring and adverse event reporting are key components of stem cell therapy. As discussed above, we maintain a comprehensive complications and outcomes tracking database with regular patient contacts.
  • The clinical outcomes (both good and bad) must be published in peer reviewed medical journals. We at RSI have already published imaging based case reports and are now moving onto clinical case series and safety studies. We are currently preparing for publication larger case series and will eventually move onto to randomized controlled placebo trials.
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Bone Marrow Nucleated Cell Concentrate (BMAC): Is it Concentrated Enough?

 

bmac machine

bmac machine

 

In 2005-2006 we mixed up BMAC in our cell biology lab.  It was easy to create from a marrow aspirate.  We performed some basic MRI studies with pre and post 3.0T high field studies and ran outcome questionnaires for knee and hip arthritis patients.  We were unimpressed by the results and because of this experience moved on to culture expanded mesenchymal stem cells.  

 

BMAC has become popular of late. In this procedure, a physician takes a bone marrow aspirate, places it in a specially designed centrifuge and pulls out a concentrate of bone marrow nucleated cells. This has been billed as a stem cell concentrate, but the stem cells that are concentrated in reasonable numbers tend to be CD34+ heme progenitors (stem cells that make new blood) and not MSC’s (Mesenchymal Stem Cells). Since MSC’s are the MVP of the adult stem cell mix available in a bone marrow concentrate, their concentration is very important to the success of such a treatment. A recent study on bedside bone marrow concentrate machines for MSC’s (BMAC) determined what concentrations were possible from a commercially available centrifuge unit. Using this study to calculate MSC numbers, a 60 ml bone marrow draw would produce 70,000-90,000 MSC’s. The Regenexx procedure yields after culture expansion are in the 5M-100M range. Based on this data, the Regenexx procedure produces approximately 100-1,000 times more cells than you can obtain with BMAC bedside systems. Based on this and other data, our best estimate is that the average micro fracture procedure would release 5-10 ml of un-concentrated marrow, so about 500-1,000 MSC’s into the defect site. Our own dosing data and the copious animal research would suggest that for appropriate cartilage, tendon, ligament, muscle repair the necessary MSC dose is in the millions range. Obtaining that amount of MSC’s from a BMAC system would require unacceptably high volumes of whole marrow from the patient. The conclusion, while very convienent, BMAC doesn’t have the right stuff.

For more information on different stem cell types, I’ve posted a video below:

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