Thx for posting this here, great article and here is the section on ACTC by Dr. Vincent for those who can not for whatever reason access it. Fabulous interview and answers many questions. ++++
Here, researchers from a dozen different groups around the world discuss their work with stem cells and the eye, explaining their goals, their reasons for choosing the types of cells they’re working with and what they’ve discovered to date.
Embryonic Stem Cells Redux
Advanced Cell Technology has begun human clinical trials of its stem cell treatment for macular degeneration in the United States. Above: The study’s principal investigator, Steven Schwartz, MD, transplants fully differentiated retinal pigment epithelial cells derived from human embryonic stem cells into a patient’s eye.
Not surprisingly, some research is farther along—especially in terms of being clinically available—than others. Advanced Cell Technology (Marlborough, Mass., and Santa Monica, Calif.) has already begun human clinical trials in the United States, injecting retinal cells derived from an embryonic stem cell line into the eye to address macular degeneration. The company is also engaged in researching other ocular and non-ocular applications for derivatives of their embryonic stem cells.
Matthew Vincent, PhD, Advanced Cell Technology’s director of business development, explains that the embryonic stem cell lines they use to make differentiated cells for transplantation are not obtained in the traditional way. “The original technique for obtaining embryonic stem cells involved isolating the inner cell mass from embryos that were left over from in vitro fertilization, embryos that were being thrown away. It was necessary to break apart the embryo, which, as everyone knows, is controversial.
“We don’t obtain our cells in that way,” he continues. “We realized that in vitro fertilization clinics had developed a technique that allows them to take a single cell from a much earlier-stage embryo and use that for genetic testing. This technique, called preimplantation genetic diagnostics, is neither destructive nor harmful to the embryos. In fact, there are 40,000 to 60,000 people in the world who had this single-cell biopsy done to them when they were only eight-cell embryos in a clinic.
“It was Robert Lanza, MD, at our company who figured out that you can take that single cell and generate an embryonic stem cell line from it,” he says. “So in 2005, we generated about a dozen embryonic stem cell lines using this non-destructive technique. By definition, these cell lines can divide indefinitely, so one single cell can now be used to make trillions of doses of retinal cells—or any other tissue in the body. Ultimately, all of our cell therapies will be derived from the embryonic stem cell lines we started back in 2005. If people come to understand this, it should help make them more comfortable with these therapies.”
Dr. Vincent says that to get the stem cells to form the desired type of tissue, they recapitulate the signals that stem cells encounter during the formation of the eye in utero. “Duplicating those in the culture dish causes the stem cells to become RPE cells,” he explains. “The result doesn’t look like an eye; we end up with sheets of lightly pigmented cells. A small, six-wall culture plate, roughly 4 x 6 inches in size, has enough surface area to manufacture 50 doses of cells. So the process can be done on a large scale in a small space. An individual dose is 50,000 to 200,000 cells; it can be cryopreserved so it’s easy to ship; and just as importantly, the injection of the cells into the patient’s eye uses a standard, off-the-shelf cannula, which most eye surgeons are familiar with. The entire procedure, including the vitrectomy, takes 90 to 120 seconds. It’s very straightforward.”
Embryonic Advantage
“We’re currently deriving a number of different tissues from our embryonic stem cell lines that we hope can be used to either reduce the rate of progress of disease or repair and regenerate tissue that’s been damaged by disease such as macular degeneration,” he continues. “Our rationale for treating the RPE is that it serves a host of important functions. It secretes trophic factors that support the photoreceptors; it’s involved in detoxifying the back of the eye; it secretes a basement membrane and is responsible for the health of Bruch’s membrane, the loss of which leads to wet macular degeneration; and it’s pigmented, so it both protects the underlying capillary bed from UV radiation and absorbs light that isn’t absorbed by the photoreceptors, preventing backscatter and thus improving visual acuity. We think that replacing missing RPE cells is the right approach to treating a variety of diseases.”
Dr. Vincent notes several advantages to using embryonic stem cells rather than other alternatives. “One of the things that’s unique to an embryonic stem cell is that when you first derive it, it’s fetal tissue,” he says. “So the RPE cells we make for treating macular degeneration resemble very young RPE cells, like those you’d find in a newborn or a fetus. Their viability, potency, ability to engraft and ability to engage in the normal function of the tissue is much more robust, typically, than the same cell that you might make from an adult source of stem cells.” Dr. Vincent admits that embryonic stem cells are not ideally suited for every situation. “Induced pluripotent stem cells make sense when you need patient-specific stem cells,” he says. “We’ve focused on diseases in which allogeneic tissue—tissue from another donor—is appropriate. It’s going into a space in the body that’s generally immune-privileged, where the immune system won’t see it and reject it. But there are a lot of other tissues such as heart or pancreas where that’s not a practical strategy. Because our cells don’t need to be generated from the patient, they represent a more commercially tractable model, but iPS cells will still play a big role in stem cell therapies.
“In the meantime, however, there are still issues with iPS technology that need to be resolved,” he says. “For example, embryonic stem cells can divide indefinitely, but iPS lines will typically stop dividing after two to 20 passages. You also see a high level of mutation occurring in a lot of iPS lines, and some lines have displayed a problem called epigenetic memory, where some of the cells spontaneously differentiate back to the type of tissue you made them from. The science is intriguing, but I think the reality is that we still have a ways to go before that approach is perfected.”
He notes that it’s a huge advantage that the RPE layer is immune-privileged. “That means you don’t have to match the donor cells with the patient’s, so you can create a therapy that you can manufacture in one place, store and then ship to the clinics where it will be injected,” he says. “You don’t have to go through the process of trying to match up donors or harvest tissue from the patient to make new RPE cells.
A miniature human optic cup grown from embryonic stem cells, containing a layer of light-responsive photoreceptor cells. Grown in vitro without blood circulation, these “organ buds” can only reach a few millimeters in diameter. “The other big advantage of treating the RPE,” he adds, “is that the fovea, where the image is formed, is only about 60,000 cells in surface area. So we’re talking about injecting a relatively small number of cells.”
Early Results
Dr. Vincent says early results of the current trials have already been published. “We have a dry macular degeneration trial and a Stargardt’s macular dystrophy trial in the United States, and a Stargardt’s trial in Europe,” he notes. “The results so far have confirmed the treatment’s safety; we’ve seen no evidence of inflammation or formation of the wrong types of tissue. We’ve now treated a total of nine patients with the same result—no adverse effects whatsoever.
“Even though these are Phase I studies, we’d hoped that we could find some evidence that the cells were surviving, engrafting at the right anatomical location and persisting,” he says. “In each case we’re dealing with late-stage patients, so we didn’t expect to see any impact on their visual acuity. Now, with more than a year of data on our first two patients, we’ve seen evidence of engrafting and persistence—and we’ve also seen both subjective and objective evidence of improved visual acuity across the board, for all patients. Subjectively, patients are telling us that they have better contrast sensitivity. In some cases colors that had faded, particularly in Stargardt’s patients, have started to come back. And in many cases we’ve seen measurable changes in visual acuity.”
Dr. Vincent says the first Stargardt’s patient went from hand motion only to being able to read three lines on an eye chart. “That improvement has persisted for 12 months,” he adds. “So we’re seeing functional evidence that the cells are doing what they’re supposed to do, and it’s persisting for a long time. If this therapy works the way we hope it does, it’s conceivable that patients might only have to go back and get a cell injection once every couple of years. Some patients might be able to go a lifetime with a single injection.
“Our end goal is to get this product to the point at which it can be used in patients who are just beginning to have signs of these diseases,” he says. “We’d like to resurface, and as a consequence recapitulate, the structure of the RPE layer before there’s been any substantial loss of photoreceptors.”
Dr. Vincent adds that the company is also making a number of other cells for use in the eye. “We have a brand new type of photoreceptor progenitor cell that we’re excited about,” he says. “This one has characteristics that have not previously been described in the literature. It can form either rods or cones, and because it’s fully differentiated when we inject it, it’s extremely unlikely to turn into a different type of tissue. We think that from a safety perspective, this is the appropriate candidate cell to use in late-stage macular degenerative disorders, where you want to be able to replace photoreceptors that were lost.
“We’ve also been working on a number of protein therapeutics that have potentially neuroprotective and maybe even regenerative capabilities with regard to photoreceptors and other layers of the eye,” he adds. “These are not cell therapies, but biologics. They reduce the impact of stress on the photoreceptors, and may possibly trigger regeneration. And, we have a corneal endothelium program. We can now make corneal endothelial cells capable of secreting Descemet’s membrane and forming sheets of cells in the culture dish. This is currently in animal studies, and we’ve seen a lot of encouraging results to date.”
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