The Food and Drug Administration has cleared Geron, a stem cell company based in Menlo Park, CA, to move forward with clinical tests of its experimental cell therapy for spinal cord injury, which is derived from embryonic stem cells. The company, which has been working on cell based therapies for the last decade, first won permission to begin clinical testing in January of 2009. But the trials were put on hold last August due to new safety concerns from animal tests. The clinical trial marks the first human tests of a therapy derived from embryonic stem cells.

The cell therapy, called GRNOPC1, is made by transforming embryonic stem cells into oligodendrocytes--a type of brain cell that wraps itself around neurons, forming a fatty insulation layer that allows electrical messages to be conducted throughout the nervous system. In many spinal-cord injuries, these cells are damaged, but the underlying nerve cells remain intact. The new cells are then injected into the site of the injury, coating exposed nerves and restoring communication to the nervous system.

As I noted in a previous post:

Scientists published the results of a successful study testing the therapy in animals in 2005, showing that paralyzed rats injected with the cells were able to walk again. Since then, Geron has been conducting numerous studies intended to show the safety of the cell-based therapy, as well as developing production methods that would make the cells as easy to use as more traditional treatments. Geron researchers have also developed a way to reliably freeze and thaw brain cells, so that they can be manufactured in a central location, and then shipped to the hospitals where they will be used.

According to a statement from Geron:

The clinical hold was placed following results from a single preclinical animal study in which Geron observed a higher frequency of small cysts within the injury site in the spinal cord of animals injected with GRNOPC1 than had previously been noted in numerous foregoing studies. In response to those results, Geron developed new markers and assays as additional release specifications for GRNOPC1. The company completed an additional confirmatory preclinical animal study to test the new markers and assays, and subsequently submitted a request to the FDA for the clinical hold to be lifted.

Advanced Cell Technology, a stem cell company based in Marlborough, MA, hopes to follow Geron. The company announced this week that it has submitted new materials to the FDA in regards to its application, first filed in November, to begin clinical trials of a cell therapy for patients with Stargardt's Macular Dystrophy, an inherited eye disease.

The image shows the development of a human-bovine cloned embryo (top) and a human-rabbit cloned embryo (bottom). Credit: CLONING AND STEM CELLS, 2009 Mary Ann Liebert Inc.

A shortage of human eggs has been the major impediment to human cloning, so scientists have been trying to use animal eggs instead, a controversial approach that has raised fears of human-animal hybrids. Now new research suggests that using animal eggs as surrogates won't be successful.

In therapeutic cloning (or somatic cell nuclear transfer), scientists transplant DNA from an adult skin cell into an egg that has had its DNA removed. Unknown factors in the egg reprogram the adult DNA to resemble embryonic DNA, and, in theory, the cell begins to develop like a normal embryo. Scientists would like to create stem cells from cloned human embryos, both for research and potentially for therapy: the cells would be genetically matched to their human donors and thus could be transplanted without fear of rejection. But no one has yet accomplished this with human cells and eggs.

The creation of human-animal hybrids has been a subject of great debate in the United Kingdom, where scientists won permission to use rabbit and cow eggs in human cloning experiments in 2007. (This Q&A with Ian Wilmut, the biologist who spearheaded the cloning of the now renowned sheep Dolly, explores the controversy.) Similar research involving rabbit eggs has taken place in the United States, but with little government regulation here, there has been much less public debate.

A paper published today in Cloning and Stem Cells could make the debate moot. A comparison of gene expression in human cells transplanted into both human eggs and animal eggs suggests that animal eggs simply don't have the power to reprogram human DNA. Here's an extract from a press release issued by Advanced Cell Technology (ACT), which sponsored the research.

Although human-to-human clones (human clones) and human-to-animal clones (hybrids) appear similar, the pattern of reprogramming of the donor human cell is dramatically different. This study . . . shows for the first time that the donor DNA in the cloned human embryos is extensively reprogrammed through extensive up-regulation ("turning on" of genes) with similar expression patterns to normal human embryos. Nearly all of the key differentially-expressed genes were activated in the human clones. In distinct contrast, the majority of these genes were down-regulated or silenced in the human-animal hybrids.

Wilmut, who edits the journal, said in a statement, "This very important paper suggests that livestock oocytes are extremely unlikely to be suitable as recipients for use in human nuclear transfer. This is very disappointing because it would mean that production of patient-specific stem cells by this means would be impracticable."

In the last year, scientists have been experimenting with a new method of reprogramming, which skips the egg altogether and instead uses several genetic factors to directly modify DNA. The ACT researchers also examined expression of these key genes and found that they were activated in both normal and cloned human embryos but not in the human-animal hybrids. "The human-animal hybrids showed no difference or a down-regulation of these critical pluripotency genes--effectively silencing them--thus making the generation of stem cells impossible. Without appropriate reprogramming, these data call into question the potential use of animal-egg sources to generate patient-specific stem cells," said Robert Lanza, chief scientific officer at ACT, in an e-mail.

Some say that the characterization of reprogramming in human clones is the most interesting aspect of the research. According to an article in the Scientist,

The gene expression profiles now "lay the foundation" for other detailed molecular analyses of human-human clones with an eye toward isolating embryonic stem cells, said [Keith Latham, a developmental biologist at Temple University School of Medicine, in Philadelphia, who was not involved in the research]. [Justin St. John of Warwick University] agreed that the paper's most important finding was the detailed characterization of human-human embryos, not the limited human-animal hybrid data. "That in and of itself is a success," he said. "I'm not sure why they weren't selling that point more . . . They seem to [be] spinning a negative result instead of spinning [a] positive result."