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Archive for the ‘stem cell’ Category

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

Converting skin cells to beating heart cells in just 11 days

 :: Posted by American Biotechnologist on 01-31-2011

Scripps Research Institute scientists have converted adult skin cells directly into beating heart cells efficiently without having to first go through the laborious process of generating embryonic-like stem cells. The powerful general technology platform could lead to new treatments for a range of diseases and injuries involving cell loss or damage, such as heart disease, Parkinson’s, and Alzheimer’s disease.

The work was published January 30, 2011, in an advance, online issue of Nature Cell Biology.

“This work represents a new paradigm in stem cell reprogramming,” said Scripps Research Associate Professor Sheng Ding, Ph.D., who led the study. “We hope it helps overcome major safety and other technical hurdles currently associated with some types of stem cell therapies.”

The advantages of producing heart cells directly from skin cells while circumventing the normal route of reprogramming them first into induced pluripotent stem cells (iPS) include:

  • saving the 2 to 4 weeks needed for the iPS reprogramming step
  • saving 2 to 4 weeks needed to convert the iPS cells into heart cells
  • avoiding the chance that undifferentiated iPS cells remain with the potential of becoming cancerous later on
  • going from skin cells to beating heart cells in a dish in just 11 days
  • The converted skin cells beat much like seen in the video below. However, unlike the video which shows reprogrammed adult cells that have become beating heart tissue, the team introduced the same four genes initially used to make iPS cells into adult skin fibroblast cells, but instead of letting the genes be continuously active in cells for several weeks, they switched off their activities just after a few days, long before the cells had turned into iPS cells. Once the four genes were switched off, the scientists gave a signal to the cells to make them turn into heart cells.

    (Video Citation: “Functional Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells.” By Jianhua Zhang, Gisela F Wilson, Andrew G Soerens, Chad H Koonce, Junying Yu, Sean P Palecek, James A Thomson, and Timothy J Kamp. Circulation Research, Vol. 104 No. 3, Feb. 12, 2009.)

    For a great tool on stem cells, be sure to download the Stem Cell Guide for Life Science Reserchers from Bio-Rad Laboratories.

    Click here to read the full press release from the Scripps Research Institute.

Twenty-two months in the making…World’s first embryonic stem cell trial begins

 :: Posted by American Biotechnologist on 10-18-2010

Last week Geron announced the enrollment of the first patient in the company’s clinical trial of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells, GRNOPC1.

The primary objective of this Phase I study is to assess the safety and tolerability of GRNOPC1 in patients with complete American Spinal Injury Association (ASIA) Impairment Scale grade A thoracic spinal cord injuries. The study represents the word’s first clinical embryonic stem cell trial and occurs eleven years after the company started working with hESCs and twenty two months after the trial was first approved by the Food and Drug Administration.

On January 23, 2009 the FDA approved the world’s first test in people of a therapy derived from human embryonic stem cells. The phase I trial was approved for Geron Corp to inject stem cells into 8 to 10 spinal cord injury patients 7 to 14 days after the injury occurs. Geron’s therapy involves using various growth factors to turn embryonic stem cells into precursors of neural support cells called oligodendrocytes, which are then injected into the spinal cord at the site of the injury.

The therapy was developed in collaboration with Hans Keirstead of the University of California, Irvine who published a paper in the May 11 issue of The Journal of Neuroscience which demonstrated that human embryonic stem cells were successful in restoring the insulation tissue for neurons in rats treated seven days after spinal cord injury, which led to a recovery of motor skills.

Below is a video of Hans Keirstead’s reaction to news that the FDA approved the world’s first embryonic stem cell therapy study in humans.

According to Geron’s latest press release:
“Initiating the GRNOPC1 clinical trial is a milestone for the field of human embryonic stem cell-based therapies,” said Thomas B. Okarma, Ph.D., M.D., Geron’s president and CEO. “When we started working with hESCs in 1999, many predicted that it would be a number of decades before a cell therapy would be approved for human clinical trials. This accomplishment results from extensive research and development and a succession of inventive steps to enable production of cGMP master cell banks, scalable manufacture of differentiated cell product, and preclinical studies in vitro and in animal models of spinal cord injury, leading to concurrence by the FDA to initiate the clinical trial.”

For a great primer on stem cell research download the free guide:Stem Cell Basics for Life Science Researchers from Bio-Rad Laboratories.

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?