An eye to stem cell therapies (Stem Cell Special Report Part 1)

Despite the renewed research interests in stem cells, therapeutics push the market

Randall Willis
Sarah had always been squeamish when it came to her eyes.Eyeliner application took forever, and contact lenses had always been out ofthe question. So the thought of someone sticking a needle in her eye made herstomach 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. Shehoped so. Watching her grandchildren grow up was riding on it.
Another 1.8 million Americans are potentially in the sameboat as Sarah as they, too, deal with the relentless onset of age-relatedmacular degeneration (AMD) and look to new therapies such as stem cell-basedregimens 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 tofacilitate a better understanding of disease pathologies—the so-called "diseasein a dish"—and to develop cell-based assays for traditional drug developmentand safety monitoring (see "Model citizens," DDNews August 2013). But alongside this renewed research focus, astypified by the many presentations and companies at the recent InternationalSociety for Stem Cell Research (ISSCR) conference in Boston, is a continued focuson the therapeutic potential of stem cells.
For people like Martin McGlynn, president and CEO of StemCells Inc., and Matthew Vincent, director of business development at AdvancedCell Technologies (ACT), the difference in focus can be summed up to a significantlevel as the difference between academic and industrial research.
"I think it is fair to say that, in settings of academicresearch reflected in the ISSCR poster sessions, there has been a robust focusor refocus on basic research," says Vincent.
"Yamanaka's discovery of iPSC [induced pluripotent stemcell]—the ability to dedifferentiate and reprogram cells—came like manna fromheaven because it presented the research community with the opportunity tocontinue to understand and study disease, and also to potentially evaluate theuse of cells derived from an iPSC platform for therapeutic uses," echoesMcGlynn.
It also alleviated a lot of the religious and social andethical baggage that came along with embryonic stem cell (ESC) research, hesuggests, particularly in the United States.
By the same token, Vincent warns, iPSC technologies are notas mature as human embryonic stem cell (hESC)-based efforts.
"A second large focus of basic research seems to be centeredon both comparing the use of iPSC cells with human ESCs, and solving the iPSCissues—the latter being an effort to figure out how to take theless-than-perfect reprogramming in iPSC that is scattered throughout theliterature, and all of the reported problems that come with issues such asepigenetic memory and developing better induction technology," he says.
By comparison to the ISSCR membership, which McGlynndescribes as predominantly academic, he points to the membership of theAlliance for Regenerative Medicine (ARM), which is almost exclusivelycommercial.
"Cell therapy is a major component of the regenerativemedicine sphere," he says. "If you look at the ARM membership, about 60 percentof them are in cell therapy. Gene therapy would represent about 8 percent.Tissue engineering is probably the second largest with about 27 percent ofmembers."
As shown in the charts from the most recent ARM AnnualReport, these companies are currently in the middle of more than 300 clinicaltrials of cell-based therapies for a variety of disorders ranging from cancerto autoimmunity to metabolic disorders.

"Over 200 companies are now involved in early-, mid- andlate-stage clinical trials in the whole field," McGlynn says. "I think it's asafe bet there's going to be some very encouraging data that will emerge fromnot all, but some or many, of these trials that will add further impetus to thewhole field of regenerative medicine."
That data will no doubt have a significant impact on wherethe stem cell market goes over the next few years.
According to a 2012 report from BCC Research, the majormarket for stem cells will be their use in the treatment of disease, and thereis already a population of companies specializing in developing stem cellsdirected toward specific disease targets. They valued the global market forstem cells at $3.8 billion in 2011 and suggested it could reach $6.6 billion in2016, reflecting a five-year compound annual growth rate of 11.7 percent.
The report is somewhat more cautious than McGlynn, andconsiders the market opportunity to still be largely at an early, experimentalstage, with the exception of the use of stem cells taken from a patient's ownbone 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 alsoproviding 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 stemcells, for the non-therapeutic use of cells and reagents to help thepharmaceutical industry and others to use cells as assays and tools to helpthem figure out potential uses for small molecules to treat disorders of theCNS," McGlynn explains. "We saw a niche opportunity to further develop and growa specialty cell culture reagents business. In turn, we also added various celllines, kits involving reagents and cells, and the antibodies that are used totrack stem cells."
While the services division—based in Cambridge, U.K.—hasseen double-digit sales growth year-on-year, McGlynn suggests it remains arelatively small business within Stem Cells Inc., a boutique specialty reagentsbusiness that will never turn the company into a profitable business entity inand of its own right.
"It certainly will contribute to reducing our demand andappetite for cash to fund our R&D on therapeutics, but quite frankly, it doesn'thave the scale to counterbalance the entire burn."
For McGlynn, the services arm of the company is moreimportant 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 intherapeutics, it helps us learn and provides insight to where the field isgoing," he explains.
Those connections continue to pay off for Stem Cells Inc.,which McGlynn describes as the leading stem cell therapy company that isfocused on the use of cells for diseases and disorders of the CNS, includingbrain disorders, spinal cord injury and ocular diseases. 
"Our business model is based on stem cells in a bottle," heexplains, describing the company's homologous cell platform, taking cells fromthe 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. Versusan autologous or patient-specific approach, which really has a significantchallenge in terms of scalability, obviously, as well as a process delay toallow 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 thepatient, 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 bepredifferentiated into the progenitor cell of interest.  If you're interested in transplanting neuronsor 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 cellbefore 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 cellsof that organ system.
"In vivo, when youput these brain tissue-derived, hard-wired cells back into the brain, they areregulated by the host and give rise to the particular cell that the hostdetermines it needs," he adds. "They do it because they are the naturallyoccurring cells, the building blocks of that organ system, and they go to workunder the regulation of the host."
Patient safety is also another huge reason why Stem CellsInc. follows a homologous approach.
"Once you extract these cells from tissue, they can bedirectly transplanted into the patient, unlike the human ESCs which gives riseto a tumor if it's transplanted into a patient without first differentiating itinto a particular kind of neuron," McGlynn says. "Then—and this is the criticalstep—making sure that this population of neurons that is to be transplanted iscompletely free of even one ESC, because that's all it takes. One ESC that willgive rise to every cell in the body, and when you transplant anundifferentiated, unpurified cell that comes from an embryonic source and putit into the brain, you can get a really bad teratoma. You don't have thatchallenge with a homologous approach." 
At least at this stage in their development, iPSCs aren'tthe answer either, as he believes they suffer from the same issues as ESCs.
"The tumorigenicity question will really need to be wrestledto the ground before these cells could even be considered as potentially usefulin therapeutic approaches, albeit they don't have the religious or ethicalbaggage 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 andend-all, according to ACT's Vincent, who uses the example of mesenchymal stemcells (MSCs).
"MSCs have a limited replicative capacity, so [they] are notself-renewing," he says, explaining why ACT has gone the route of manufacturingcell therapies using its hESC lines, which were derived using the company'sproprietary single blastomere technology that does not destroy nor harmembryos, to some extent doing an end-run around the ethical dilemmas associatedwith hESCs.
"In our hands, transplantable tissues and cells that we makefrom hESC lines are more robust, potent and durable than the equivalent tissueisolated from adult sources," Vincent says.
Likewise, the company isn't ignoring the potential of iPSCsto provide downstream therapeutic opportunities.
"The ultimate goal with iPS cells is to create an embryonicstem cell by inducing dedifferentiation of adult tissues," he says. "Thisoffers a wonderful opportunity to create patient-specific pluripotent celllines. The current variations to the iPS technology are vast, and the stabilityand pluripotency of the resulting lines equally diffuse, so much work isrequired to elucidate which technologies are best suited for use in humantherapeutic products. We have narrowed our search for suitable technologies, aswell as work on improvements, as we bring iPS forward as an additionalmanufacturing platform."
Vincent suggests there is a significant bottleneck in theavailability of MSCs for use in ongoing trials. ACT has been working to addressthat sourcing problem by making MSCs from an inexhaustible startingmaterial—hESCs or iPSCs.
"Not only did we succeed in generating commercial-scalemanufacturing of MSCs from these stem cell sources, but we discovered that ourMSCs were far more potent at reducing inflammatory components of variousdiseases than equivalent doses of adult-derived MSCs," he says.
Vincent recognizes the safety concerns raised above byMcGlynn, and in fact, at least in part, it was those concerns that led ACT tochoose its therapeutic target—the eye.
"One way that we were able to mitigate the challenges was bytreating patients with a small amount of cells first, and injecting those cellsinto the area of the body where we believed they would remain localized,"Vincent explains. "Also, it was important to be able to show improvement inpatients in distinct ways to understand the full value to the medicalcommunity. The transparency of the front of the eye meant that we could observewhat happened to the injected cells in a non-invasive manner using standardtools that ophthalmologists use regularly. Working in diseases of the eye meantthat we could treat patients with as little as 50,000 cells and see signs ofimprovement in their condition. AMD was a clear choice due to its degenerativenature and our cells' function to regenerate tissue."
He also suggests that as AMD is a $25 billion- to $30billion-market in the United States and Europe alone, the medical need isobvious and dramatic. Another condition ACT is targeting—Stargardt's maculardystrophy, which affects children and young adults—is less common, but thebiology of the disease and lack of available treatments for patients made itattractive to the company.
"Our ongoing clinical trials in which we transplant humanretinal pigment epithelium (RPE) cells in patients with various forms ofmacular degeneration utilize one of our hESC lines," he says. "At the time wewere starting this program, we had derived a number of hESC lines through oursingle blastomere technique."
In the off-the-shelf model described by McGlynn, Vincentsays ACT generated a GMP-compliant master cell bank and conducted itspreclinical studies with RPE cells from that bank, adding that during thisperiod, iPSC lines were not yet available in a way that would have permittedthe company to gain U.S. Food and Drug Administration approval for humantesting.
"Our RPE program is currently in three clinical trialsacross the U.S. and Europe, with patient enrollment more than halfwaycomplete," he says. "We published the findings from the first two patients in The Lancet in early 2012, which showedunprecedented improvement by patients treated with the lowest dose. The effectson visual acuity have been persistent, with our longest patients being followedfor more than two years now. We recently reported that our clinicians observedin an increase in visual acuity after treatment for one of our dry AMD patientsfrom 20/400 to 20/40. That improvement has been sustained for the more thanfour months since that patient was treated." 
Suppress to impress
Both Stem Cells Inc. and ACT have chosen to go theallogeneic route in their therapeutic strategies, providing patients with cellsfrom donors rather than from the patient him or herself (autologous), a choicethat makes sense for ARM Chairman and Organogenesis President and CEO GeoffMacKay.
"If an allogeneic therapy can work in lieu of an autologoustherapy, it absolutely should be used," MacKay told Streetwise Reports in April, echoing McGlynn's sentiments. "Anallogeneic product can be mass-produced, industrialized and delivered to aclinic at a price point that is comparable to other healthcare modalities, andthat is significantly more convenient than autologous therapies."
MacKay acknowledged that some therapeutic applications willdemand an autologous approach, predominantly for immunological reasons, but hecautioned that the unmet need must be rather dramatic because of the highercosts and inconvenience associated with an autologous regimen.
"Unmet medical need and the willingness of payers to paymust be well understood prior to embarking on this technology," he added.
As MacKay suggested, immune response has been a majorrallying cry for those in the autologous regimen camp as companies andclinicians raise concerns about the need for onerous and potentially hazardousimmunosuppression in patients receiving cells from donors. McGlynn agrees thatthis concern is valid but that it can be tempered somewhat by advancements madein immunosuppression regimens.
"The immunosuppression regimens that we use are nothing likethe full-bore regimens that you see in organ transplants," he offers. "Thetechniques have become very exquisite, finely tuned, and they're temporary—12months or less."
McGlynn suggest there will be a general move away fromsystemic immunosuppression regimens to more localized regimens that will have asignificantly less dramatic impact on the patient. Again, the therapeutictarget may have a lot to do with that.
"An obvious example of that would be that you couldtranslate forward in the eye from a systemic immunosuppression regimen to alocalized 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 becomemore attractive to payors.
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