Posts Tagged ‘stem cell research’

Moving gene therapy one step closer to clinical reality

 :: Posted by American Biotechnologist on 04-05-2011

Scientists from the Morgridge Institute for Research, the University of Wisconsin-Madison, the University of California and the WiCell Research Institute moved gene therapy one step closer to clinical reality by determining that the process of correcting a genetic defect does not substantially increase the number of potentially cancer-causing mutations in induced pluripotent stem cells.

Their work, published in the online edition of the journal Proceedings of the National Academy of Sciences and funded by a Wynn-Gund Translational Award from the Foundation Fighting Blindness, suggests that human induced pluripotent stem cells (iPS) altered to correct a genetic defect may be cultured into subsequent generations of cells that remain free of the initial disease.

However, although the gene correction itself does not increase the instability or the number of observed mutations in the cells, the study reinforced other recent findings that induced pluripotent stem cells themselves carry a significant number of genetic mutations.

In brief, scientists produced iPS cells by episomal reprogramming, corrected a disease-causing mutation by homologous recombination and removed the puromycin cassette that was used for gene selection using Cre recombinase.

Results of the study indicate that both homozygous recombination and cassette removal did not increase the iPS mutational load. Nonetheless, the initial induction of primary dermal fibroblasts into iPS cells lead to a fairly substantial mutational load at the time of derivation.

This study is important in that it demonstrated that downstream cloning events do not introduce further mutations into iPS cells which can be a source of tremendous therapeutic value. Nonetheless, it is important for further studies to focus on reducing mutational events caused by iPS induction which may be a serious drawback to introducing iPS therapy into the clinic.


Howden S et al, (2011) Genetic correction and analysis of induced pluripotentstem cells from a patient with gyrate atrophy. PNAS



But are they really pluripotent?

 :: Posted by American Biotechnologist on 03-09-2011

Scripps Research Scientists Develop New Test for “Pluripotent” Stem Cells

The diagnostic test enables accurate, rapid assessment of the quality of stem cell lines

LA JOLLA, CA – “Pluripotent” stem cells—which have the potential to mature into almost any cell in the body—are being widely studied for their role in treating a vast array of human diseases and for generating cells and tissues for transplantation. Now, a team of Scripps Research Institute scientists has created a quality control diagnostic test that will make it much easier for researchers to determine whether their cell lines are normal pluripotent cells.

The study was published in an online version of Nature Methods on March 6, 2011.

“Many scientists are unhappy with the current gold standard for testing for pluripotency, called the teratoma assay,” said Scripps Research molecular biologist Jeanne Loring, principal investigator of the study. “The teratoma assay requires animal testing and a time span of six to eight weeks before scientists can prove that they have a pluripotent stem cell line. In addition, this method is technically challenging and difficult to standardize.”

The new test, called “PluriTest,” meets the need for a cost-effective, accurate, animal-free alternative to the teratoma assay for assessing pluripotency. Using microarray technology, which enables the simultaneous analysis of thousands of different DNA sequences, the Scripps Research team created a large database of information about all the genes that are active in hundreds of normal human embryonic and induced pluripotent stem cells and a variety of non-pluripotent cell lines. For PluriTest, this database was used to create a detailed molecular model of a normal pluripotent stem cell line.

“Unlike diagnostic tests that use small sets of biomarkers to examine cells, the molecular model approach uses all of the thousands of pieces of information in a microarray,” Loring said. “This results in a diagnostic test with remarkable sensitivity and specificity.” Scientists upload raw data straight from a single microarray analysis to the PluriTest website and learn within 10 minutes whether their cell line is pluripotent.

An additional feature of the PluriTest diagnostic test is that it can show whether a cell that is pluripotent is different in some way from the normal model pluripotent cell line. For example, a “novelty score” generated by the software may indicate that the pluripotent cells have genomic aberrations such as extra copies of genes or chromosomes. This feature would alert the researcher to do additional analysis on the cells to determine what is causing the abnormality.

A first author of the study, Franz-Josef Mueller, said, “Scientists are making new induced pluripotent stem cell lines at a rapid pace to understand human disease, test new drugs, and develop regenerative therapies. Thousands of induced pluripotent stem cell lines have already been generated and soon there will be many more thousands. PluriTest is designed to enable the growth of this technology.”

Müller FJ, Schuldt BM, Williams R, Mason D, Altun G, Papapetrou EP, Danner S, Goldmann JE, Herbst A, Schmidt NO, Aldenhoff JB, Laurent LC, & Loring JF (2011). A bioinformatic assay for pluripotency in human cells. Nature methods PMID: 21378979

Source: Scripps Institute

FDA Approves First Stem Cell Clinical Trial

 :: Posted by American Biotechnologist on 08-04-2010

Late last week, Geron Corporation announced that the FDA had given the company approval to move forward with the world’s first clinical trial of a human embryonic stem cell (hESC)-based therapy.The company is hoping that its GRNOPC1 therapy will restore spinal cord function to patients with subacute spinal cord injury by injecting hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient’s injured spinal cord.

GRNOPC1, Geron’s lead hESC-based therapeutic candidate, contains hESC-derived oligodendrocyte progenitor cells that have demonstrated remyelinating and nerve growth stimulating properties leading to restoration of function in animal models of acute spinal cord injury (Journal of Neuroscience, Vol. 25, 2005).

The study had been placed in a hold pattern until recently since early results showed higher frequency of small cysts within the injury site in the spinal cord of animals injected with GRNOPC1. Further studies have demonstrated the safety of GRNOPC1 in laboratory animals prompting the FDA to grant a green light for the company to proceed with Phase 1 clinical trials.

According to Geron, in addition to spinal cord injury, GRNOPC1 may have therapeutic utility for other central nervous system indications such as Alzheimer’s Disease, Multiple Sclerosis and Canavan Disease.

The market acted quite favorably to the news with Aastrom Biosciences Inc. (NASDAQ:ASTM) and International Stem Cell Corporation (OTCBB:ISCO) stock jumping 10% and 6% respectively following Geron’s news release. A fairly comprehensive list of publicly traded stem cell companies can be found here.

For a thorough introduction to stem cells, see Bio-Rad’s Stem Cell Basics for Life Science Researchers.

Here’s he question of the day for those of you who are actively engaged in stem cell research at the bench:
Has the news of the FDA’s approval of Geron’s clinical trial given you some extra motivation at the bench or are you unfazed by the glitz and glamor of the news media coverage of this event?

Does NIH Policy Complement Obama’s Executive Order Concerning Stem Cell Research?

 :: Posted by American Biotechnologist on 06-28-2010

Here’s my question:

Barack Obama issued an executive order for removing barriers to responsible scientific research involving human stem cells. How effective do you believe that the NIH’s 2009 Guidelines on Stem Cell Research are in removing these barriers?

Please see the poll at the end of this post to cast your vote.

Here’s some background:

Yesterday I vented my frustration with the recent decision by the NIH to deny approval for the use of 47 human embryonic stem cell lines in NIH funded research. More specifically, I was frustrated by the fact that the denial was linked to the use of exculpatory language (unacceptable legal language) in the consent form used by the RGI to obtain the embryonic stem cells rather than a more conventional medical ethics question.

What struck me as even more interesting is the story behind this whole fiasco. According to the NIH, on March 9, 2009, President Barack H. Obama issued Executive Order 13505: Removing Barriers to Responsible Scientific Research Involving Human Stem Cells. The order was meant to help establish policy and procedures under which the NIH will fund such research, and to ensure that NIH-funded research in this area is ethically responsible, scientifically worthy, and conducted in accordance with applicable law. Since the procedures for receiving NIH approval of human Embryonic Stem Cells may be complicated and lengthy the NIH established a stem cell registry which would avoid burdensome and repetitive assurances from multiple funding applicants.

Now for an explanation on NIH policy and my take on how RGI ended up in this precarious position. Most of what I’m about to tell you can be found in full in the NIH document National Institutes of Health Guidelines on Human Stem Cell Research. If you want to read the story from the primary source feel free to visit the website. If you want the “version in a nutshell” peppered with some of my commentary please read on.

The NIH policy is primarily concerned with the official definition of stem cells, ethical issues such as financial gain and informed consent, pre-existing stem cell populations, “extra” embryos leftover from Pre-Implantation Genetic Diagnosis (i.e. the source of RGI’s embryos) and monitoring and enforcement of the NIH stem cell policies.

The first challenge for the NIH was to define the scope of its policy vis-a-vis stem cell types. (For a great review on the various types of stem cells be sure to download Bio-Rad’s Stem Cell Basics for Life Science Researchers.) In the end, the NIH pretty much restricted its policy to the use of human embryonic stem cells proper, which encompass “cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.”

Financial gain really deals with 2 main issues. One issue concerns the fact that the stem cell recipient (i.e. the scientist) might derive profit from developing the hESCs without the knowledge of the hESC donor which might lead to exploitative practices. The other financial concern is that scientists may use their intellectual property rights to impose conditions that significantly restrict the use of these cells in biomedical research and therefore hold back scientific progress.

The big issue that really served as the backbone to the RGI story was that of informed consent and the specific language used to obtain such consent. I believe that the standard practice of informed consent is to uphold the right of any individual to not have their biological material used in a fashion that they don’t agree with and to ensure that individuals are not coerced into participating an a research study. These policies make sense and are widely accepted by the scientific community. The problem that arises in this specific case is that the use of stem cells in scientific research has been around for over decade and numerous regulatory bodies have differed in their approach to obtaining informed consent for the use of stem cells. As such, informed consent policies and procedures vary and may lead to confusion regarding the acceptable use of stem cells that pre-exsited the NIH policy in NIH-funded research. In dealing with this problem, the NIH has declared that “applicant institutions wishing to use hESCs derived from embryos donated (in the United States) prior to the effective date of the Guidelines may either comply with Section II (A) of the Guidelines or undergo review by a Working Group of the Advisory Committee to the Director (ACD).” The “patchwork of standards” referred to in the NIH document may very well have precipitated the poorly written informed consent form used by RGI thereby rendering 47 of their cell lines ineligible for NIH funded research. Furthermore, the policy also states that informed consent needs to be obtained during the time of donation and that there needs to be a degree of separation between the physician obtaining the embryo and the scientist. This further exacerbated RGI’s predicament and made it next to impossible for them to rectify the situation ipso facto.

When looking at the number of cell lines approved by the NIH, it is striking that only 75 cell lines from a handful of scientific researcher have been approved for the registry since its implementation in December 2009. Furthermore, 48 cell lines are currently pending approval 232 are in draft status, and 48 have been rejected. While it might seem like 232 stem cell lines are a significant number to have in the pipeline, it is telling to note that the huge majority of these applications were submitted by RGI followed in large part by Harvard University. Furthermore, 47 out of the 48 stem cell lines rejected by the NIH came from RGI.

If stem cell research has been around for a decade and several other regulatory bodies such as the International Society for Stem Cell Research (ISSCR) and the National Academy of Sciences (NAS) have long been involved in regulating their use, why is the NIH’s current list so short? Furthermore, why are there only a handful of institutions submitting applications for NIH approval? This seems a bit concerning to me especially considering that the NIH is the largest funding institution in the United States.

Well…now’s your chance to vote.

How effective are NIH Guidelines in implementing Obama’s order to remove barriers to stem cell research?

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