|
An eye to stem cell therapies (Stem Cell Special Report Part 1)
September 2013
EDIT CONNECT
SHARING OPTIONS:
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 Back |
Home |
FAQs |
Search |
Submit News Release |
Site Map |
About Us |
Advertising |
Resources |
Contact Us |
Terms & Conditions |
Privacy Policy
|