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An eye to stem cell therapies (Stem Cell Special Report Part 1)
September 2013
by Randall Willis  |  Email the author


Sarah had always been squeamish when it came to her eyes. Eyeliner application took forever, and contact lenses had always been out of the question. So the thought of someone sticking a needle in her eye made her stomach churn. At the same time, she realized she was running out of options, and her eyesight would only get worse. Her doctor said the new treatment was still experimental, but they had great results in other patients in restoring visual acuity. She hoped so. Watching her grandchildren grow up was riding on it.  
Another 1.8 million Americans are potentially in the same boat as Sarah as they, too, deal with the relentless onset of age-related macular degeneration (AMD) and look to new therapies such as stem cell-based regimens to stop and potentially reverse the damage caused by the disease.  
The great divide
In last month's issue of DDNews, we looked at the resurgence of stem cell technologies in basic research to facilitate a better understanding of disease pathologies—the so-called "disease in a dish"—and to develop cell-based assays for traditional drug development and safety monitoring (see "Model citizens," DDNews August 2013). But alongside this renewed research focus, as typified by the many presentations and companies at the recent International Society for Stem Cell Research (ISSCR) conference in Boston, is a continued focus on the therapeutic potential of stem cells.  
For people like Martin McGlynn, president and CEO of Stem Cells Inc., and Matthew Vincent, director of business development at Advanced Cell Technologies (ACT), the difference in focus can be summed up to a significant level as the difference between academic and industrial research.  
"I think it is fair to say that, in settings of academic research reflected in the ISSCR poster sessions, there has been a robust focus or refocus on basic research," says Vincent. "Yamanaka's discovery of iPSC [induced pluripotent stem cell]—the ability to dedifferentiate and reprogram cells—came like manna from heaven because it presented the research community with the opportunity to continue to understand and study disease, and also to potentially evaluate the use of cells derived from an iPSC platform for therapeutic uses," echoes McGlynn.
It also alleviated a lot of the religious and social and ethical baggage that came along with embryonic stem cell (ESC) research, he suggests, particularly in the United States. By the same token, Vincent warns, iPSC technologies are not as mature as human embryonic stem cell (hESC)-based efforts.
"A second large focus of basic research seems to be centered on both comparing the use of iPSC cells with human ESCs, and solving the iPSC issues—the latter being an effort to figure out how to take the less-than-perfect reprogramming in iPSC that is scattered throughout the literature, and all of the reported problems that come with issues such as epigenetic memory and developing better induction technology," he says.  
By comparison to the ISSCR membership, which McGlynn describes as predominantly academic, he points to the membership of the Alliance for Regenerative Medicine (ARM), which is almost exclusively commercial.
"Cell therapy is a major component of the regenerative medicine sphere," he says. "If you look at the ARM membership, about 60 percent of them are in cell therapy. Gene therapy would represent about 8 percent. Tissue engineering is probably the second largest with about 27 percent of members."  
As shown in the charts from the most recent ARM Annual Report, these companies are currently in the middle of more than 300 clinical trials of cell-based therapies for a variety of disorders ranging from cancer to autoimmunity to metabolic disorders.

"Over 200 companies are now involved in early-, mid- and late-stage clinical trials in the whole field," McGlynn says. "I think it's a safe bet there's going to be some very encouraging data that will emerge from not all, but some or many, of these trials that will add further impetus to the whole field of regenerative medicine."
That data will no doubt have a significant impact on where the stem cell market goes over the next few years.  
According to a 2012 report from BCC Research, the major market for stem cells will be their use in the treatment of disease, and there is already a population of companies specializing in developing stem cells directed toward specific disease targets. They valued the global market for stem cells at $3.8 billion in 2011 and suggested it could reach $6.6 billion in 2016, reflecting a five-year compound annual growth rate of 11.7 percent.  
The report is somewhat more cautious than McGlynn, and considers the market opportunity to still be largely at an early, experimental stage, with the exception of the use of stem cells taken from a patient's own bone marrow to treat conditions such as leukemia.
Bridged efforts  
Unlike most cell-based therapy companies, Stem Cells Inc. has decided to keep its feet on both sides of the research-therapeutics divide, not only accelerating its own stem cell programs into the clinic, but also providing services to academic labs around the world.
"Back in 2008, we acquired the assets of Stem Cell Sciences, which at the time was focusing predominantly on the use of NSCs, or neural stem cells, for the non-therapeutic use of cells and reagents to help the pharmaceutical industry and others to use cells as assays and tools to help them figure out potential uses for small molecules to treat disorders of the CNS," McGlynn explains. "We saw a niche opportunity to further develop and grow a specialty cell culture reagents business. In turn, we also added various cell lines, kits involving reagents and cells, and the antibodies that are used to track stem cells."  
While the services division—based in Cambridge, U.K.—has seen double-digit sales growth year-on-year, McGlynn suggests it remains a relatively small business within Stem Cells Inc., a boutique specialty reagents business that will never turn the company into a profitable business entity in and of its own right.
"It certainly will contribute to reducing our demand and appetite for cash to fund our R&D on therapeutics, but quite frankly, it doesn't have the scale to counterbalance the entire burn."
For McGlynn, the services arm of the company is more important because it serves as an interface with academic centers.  
"It keeps us in touch with the researchers in the community, and in turn, to the extent that it has relevance for what we're doing in therapeutics, it helps us learn and provides insight to where the field is going," he explains.  
Those connections continue to pay off for Stem Cells Inc., which McGlynn describes as the leading stem cell therapy company that is focused on the use of cells for diseases and disorders of the CNS, including brain disorders, spinal cord injury and ocular diseases.
"Our business model is based on stem cells in a bottle," he explains, describing the company's homologous cell platform, taking cells from the brain and inserting them back into the brain.
"They were developed just like any other drug," he says. "They have the same scalability and the benefits of economies of scale. Versus an autologous or patient-specific approach, which really has a significant challenge in terms of scalability, obviously, as well as a process delay to allow for the period of time necessary to harvest the cells from the patient, bring them to a lab, do whatever you do with them, get them back to the patient, schedule the procedure and so on."  
The real advantage of the homologous approach, he explains, is that unlike with iPSC and ESCs, cells don't have to be manipulated ex vivo, in that they don't have to be predifferentiated into the progenitor cell of interest.  If you're interested in transplanting neurons or oligodendrocytes from an embryonic or iPSC platform, according to McGlynn, you're going to have to go through a whole series of hoops to get that cell before you transplant it into the body.  
He suggests that the company's human CNS stem cells (HuCNS-SCs) are naturally hard-wired to differentiate into the particular cells of that organ system.
"In vivo, when you put these brain tissue-derived, hard-wired cells back into the brain, they are regulated by the host and give rise to the particular cell that the host determines it needs," he adds. "They do it because they are the naturally occurring cells, the building blocks of that organ system, and they go to work under the regulation of the host." Patient safety is also another huge reason why Stem Cells Inc. follows a homologous approach.  
"Once you extract these cells from tissue, they can be directly transplanted into the patient, unlike the human ESCs which gives rise to a tumor if it's transplanted into a patient without first differentiating it into a particular kind of neuron," McGlynn says. "Then— and this is the critical step—making sure that this population of neurons that is to be transplanted is completely free of even one ESC, because that 's all it takes. One ESC that will give rise to every cell in the body, and when you transplant an undifferentiated, unpurified cell that comes from an embryonic source and put it into the brain, you can get a really bad teratoma. You don't have that challenge with a homologous approach."
At least at this stage in their development, iPSCs aren't the answer either, as he believes they suffer from the same issues as ESCs.  
"The tumorigenicity question will really need to be wrestled to the ground before these cells could even be considered as potentially useful in therapeutic approaches, albeit they don't have the religious or ethical baggage attached to the platform," he notes.  
Not everyone shares McGlynn's concerns with ESCs and iPSCs, however.  
Don't cell them short
Adult-derived cells are not necessarily the be-all and end-all, according to ACT's Vincent, who uses the example of mesenchymal stem cells (MSCs).  
"MSCs have a limited replicative capacity, so [they] are not self-renewing," he says, explaining why ACT has gone the route of manufacturing cell therapies using its hESC lines, which were derived using the company's proprietary single blastomere technology that does not destroy nor harm embryos, to some extent doing an end-run around the ethical dilemmas associated with hESCs.  
"In our hands, transplantable tissues and cells that we make from hESC lines are more robust, potent and durable than the equivalent tissue isolated from adult sources," Vincent says.
Likewise, the company isn't ignoring the potential of iPSCs to provide downstream therapeutic opportunities.  
"The ultimate goal with iPS cells is to create an embryonic stem cell by inducing dedifferentiation of adult tissues," he says. "This offers a wonderful opportunity to create patient-specific pluripotent cell lines. The current variations to the iPS technology are vast, and the stability and pluripotency of the resulting lines equally diffuse, so much work is required to elucidate which technologies are best suited for use in human therapeutic products. We have narrowed our search for suitable technologies, as well as work on improvements, as we bring iPS forward as an additional manufacturing platform."
Vincent suggests there is a significant bottleneck in the availability of MSCs for use in ongoing trials. ACT has been working to address that sourcing problem by making MSCs from an inexhaustible starting material—hESCs or iPSCs.
"Not only did we succeed in generating commercial-scale manufacturing of MSCs from these stem cell sources, but we discovered that our MSCs were far more potent at reducing inflammatory components of various diseases than equivalent doses of adult-derived MSCs," he says.  
Vincent recognizes the safety concerns raised above by McGlynn, and in fact, at least in part, it was those concerns that led ACT to choose its therapeutic target—the eye.  
"One way that we were able to mitigate the challenges was by treating patients with a small amount of cells first, and injecting those cells into the area of the body where we believed they would remain localized," Vincent explains. "Also, it was important to be able to show improvement in patients in distinct ways to understand the full value to the medical community. The transparency of the front of the eye meant that we could observe what happened to the injected cells in a non-invasive manner using standard tools that ophthalmologists use regularly. Working in diseases of the eye meant that we could treat patients with as little as 50,000 cells and see signs of improvement in their condition. AMD was a clear choice due to its degenerative nature and our cells' function to regenerate tissue."  
He also suggests that as AMD is a $25 billion- to $30 billion-market in the United States and Europe alone, the medical need is obvious and dramatic. Another condition ACT is targeting—Stargardt's macular dystrophy, which affects children and young adults—is less common, but the biology of the disease and lack of available treatments for patients made it attractive to the company.  
"Our ongoing clinical trials in which we transplant human retinal pigment epithelium (RPE) cells in patients with various forms of macular degeneration utilize one of our hESC lines," he says. "At the time we were starting this program, we had derived a number of hESC lines through our single blastomere technique."
In the off- the-shelf model described by McGlynn, Vincent says ACT generated a GMP-compliant master cell bank and conducted its preclinical studies with RPE cells from that bank, adding that during this period, iPSC lines were not yet available in a way that would have permitted the company to gain U.S. Food and Drug Administration approval for human testing.  
"Our RPE program is currently in three clinical trials across the U.S. and Europe, with patient enrollment more than halfway complete," he says. "We published the findings from the first two patients in The Lancet in early 2012, which showed unprecedented improvement by patients treated with the lowest dose. The effects on visual acuity have been persistent, with our longest patients being followed for more than two years now. We recently reported that our clinicians observed in an increase in visual acuity after treatment for one of our dry AMD patients from 20/400 to 20/40. That improvement has been sustained for the more than four months since that patient was treated."
Suppress to impress  
Both Stem Cells Inc. and ACT have chosen to go the allogeneic route in their therapeutic strategies, providing patients with cells from donors rather than from the patient him or herself (autologous), a choice that makes sense for ARM Chairman and Organogenesis President and CEO Geoff MacKay.
"If an allogeneic therapy can work in lieu of an autologous therapy, it absolutely should be used," MacKay told Streetwise Reports in April, echoing McGlynn's sentiments. "An allogeneic product can be mass-produced, industrialized and delivered to a clinic at a price point that is comparable to other healthcare modalities, and that is significantly more convenient than autologous therapies."  
MacKay acknowledged that some therapeutic applications will demand an autologous approach, predominantly for immunological reasons, but he cautioned that the unmet need must be rather dramatic because of the higher costs and inconvenience associated with an autologous regimen.
"Unmet medical need and the willingness of payers to pay must be well understood prior to embarking on this technology," he added.
As MacKay suggested, immune response has been a major rallying cry for those in the autologous regimen camp as companies and clinicians raise concerns about the need for onerous and potentially hazardous immunosuppression in patients receiving cells from donors. McGlynn agrees that this concern is valid but that it can be tempered somewhat by advancements made in immunosuppression regimens.  
"The immunosuppression regimens that we use are nothing like the full-bore regimens that you see in organ transplants," he offers. "The techniques have become very exquisite, finely tuned, and they're temporary—12 months or less."  
McGlynn suggest there will be a general move away from systemic immunosuppression regimens to more localized regimens that will have a significantly less dramatic impact on the patient. Again, the therapeutic target may have a lot to do with that.
"An obvious example of that would be that you could translate forward in the eye from a systemic immunosuppression regimen to a localized administration of an immunosuppression agent just into the eye," McGlynn says.  
By potentially increasing the safety of these treatments, alongside showing significant efficacy, stem cell therapies may also become more attractive to payors.
Code: E091329



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