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SPECIAL REPORT: Regenerating interest in stem cell medicine (PART 2)
August 2012
EDIT CONNECT
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A body of work
The longtime goal of regenerative medicine has
been to
discover ways to either replace endogenous tissue functions with exogenous
cells, or to at least give the body an opportunity to heal itself
through the
stimulation and support of endogenous repair functions. Thus, stem cell-based
therapies have been developed that target an array of
conditions.
One area that has proven to be a success story for regenerative
medicine has been wound
healing, although much of the earlier efforts were
focused on the cell-based engineering of skin replacements. Companies like
Organogenesis, based in Canton, Mass., continue to pioneer the field of skin
replacement—in this case, with its Apligraf technology, which is essentially
skin grown in a Petri dish.
Similarly, Columbia, Md.-based Osiris
Therapeutics has
leveraged its growing expertise in stem cell technologies to develop Grafix
skin replacement technology, whereby MSCs are cultured
with growth factors and
a natural scaffold known as an extracellular matrix to form newly generated
skin.
MacroCure took a slightly different route, however, when it
developed its CureXcell technology, which is currently on the
market in Israel.
Rather than produce a skin replacement, MacroCure developed a cell-based
therapy that stimulates cells within the wound to initiate
its own repair.
"We like to think of skin substitutes such as Apligraf as
healing from the
outside in, whereas CureXcell is more about healing from the
inside out," explains Mashiach. "CureXcell is a full, systemic approach using a
cocktail
of cells harvested from whole blood, which are injected into the wound
and trigger a cascade of cellular functions that promote angiogenesis and the
formation of new collagen."
In CureXcell, the cells are activated to maintain their potency
before being injected into the wound tissue, where they trigger a cascade that
first re-establishes hemostasis, then inhibits inflammation, promotes
revascularization of the tissues and finally stimulates collagen production and
wound healing.
"We're currently enrolling patients in a Phase III study in
the United States with a commitment from the FDA to speed the product to
approval
if it meets its clinical criteria, and CureXcell has been tested in
more than 5,000 patients in Israel on a variety of wound types," says Mashiach.
Nerves of steel
Another area of intense interest and significant unmet
medical need is the treatment of neurological conditions, such as ALS,
Parkinson's
disease (PD) and the effects of stroke.
Using an autologous approach, BrainStorm has developed the
NurOwn system to target conditions such as
ALS, PD and multiple sclerosis. MSCs
from a patient's bone marrow are induced to produce neurotrophic factors. These
cells are then transplanted back
into the patient near the site of damage,
where they stimulate local neuronal growth and hopefully slow or stop damage
progression.
According to company CEO Adrian Hurel, the company is
currently conducting Phase I/II safety studies in Israel in
patients with both
late- and early-stage ALS, and recently entered into a memorandum of
understanding with institutes in Massachusetts to conduct Phase
II ALS studies
they hope to initiate in late 2012.
In the United Kingdom, meanwhile, ReNeuron
recently
initiated clinical testing (the Pilot Investigation of Stem Cells in Stroke, or
PISCES, study) of its allogeneic neural stem cell technology in patients
disabled by stroke. Starting with a fetal progenitor source back in 2003, the
company screened a variety of immortalized cell lines to identify
potential
therapeutic candidates, cells targeting stroke-related damage being the
strongest initial candidate.
In a June release describing early data from the first
patients in the PISCES study, principal investigator and neuroscientist
Keith
Muir of the University of Glasgow said, "The data indicate
that the ReN001 treatment has a good safety profile at
the doses administered thus far. The preliminary signals of potential
functional benefit,
whilst intriguing, will require further investigation in a
suitably designed Phase II efficacy study."
At its heart
Given the
increasingly aging population coping with
conditions such as obesity and cardiovascular disease, this disease area has
become a target for intensive
research in stem cell-based therapies.
In July, Los Angeles-based Capricor announced it had
received FDA approval to initiate the Phase II ALLSTAR
clinical trial of its
Intensicor system in patients following large myocardial infarctions (MIs).
With Intensicor, cardiac-derived stem cells (CDCs)
are cultured from donor
hearts that could not be used for transplantation (allogeneic) or biopsied
heart tissue from the patient (autologous), and then
reinjected into the
damaged heart muscle to stimulate cardiac regeneration.
In a similar manner,
Cleveland's Athersys has developed the
MultiStem system to
treat damage following MI, as well as other conditions.
MultiStem relies on allogeneic stem cells isolated from bone marrow or other
non-embryonic
tissues that are introduced to ischemic regions of the heart through
a catheter. The company's Phase I study, published earlier this year, showed
significant improvement in cardiac function following MI without any safety
concerns.
Cardiovascular disease doesn't just impact the heart,
however, as events involving the heart can have significant impact elsewhere in
the body,
such as the kidneys. As described by Brenner, cardiac interventions
such as the use of specific contrast agents or bypass machinery can trigger
acute
kidney injury (AKI).
Using MSCs derived from allogeneic bone marrow, AlloCure
induces the cells
to secrete a variety of growth factors and anti-inflammatory
factors upon introduction to the damaged tissue, triggering repair through the
growth of
new cells and blood vessels. In November, the company presented
findings of a Phase I safety and efficacy trial, showing that treatment not
only
lowered the incidence of AKI in cardiac surgery patients, but also
shortened hospital stays and reduced hospital readmission rates. A Phase II
study
was underway as we went to press, with results from more than 200
patients expected in early 2014.
Sweet surrender
The
so-called obesity epidemic has also triggered a growing
problem—at least in the developed world—of diabetes, an area that is actively
being explored by
a number of companies.
Type 1 diabetes is an autoimmune disease in which the
insulin-producing
cells in the pancreas are specifically attacked and
destroyed. The autoimmune aspect of the condition complicates its treatment, explains
Sarah Ferber,
chief scientific officer and founder of White Plains, N.Y.-based
Orgenesis, as any healthy pancreatic cells introduced into the body would
simply be destroyed.
For this reason, Orgenesis focused its efforts on the
conversion of autologous liver cells into insulin-producing cells that could be
reimplanted in
the liver to essentially replace the missing functions of the
pancreas.
"Liver is
developmentally related to the pancreas and both
tissues are sensitive to glucose," she explains. "In addition, liver has a substantial
regenerative
capacity and functional redundancy."
While an unusual approach for most cell-based therapies,
there is evolutionary precedent for this diabetic multi-organ shell game.
Several organisms (e.g., eels and
worms), Ferber explains, do not
have a separate liver and pancreas, but rather
a single organ called the hepatopancreas.
The company is
still in the preclinical proof-of-concept
phase, but has initiated conversations with regulators about proceeding to
clinical trial.
Like cardiac disease, diabetes does not simply limit its
effects to the blood sugar and energy levels, but can
also have secondary
impacts, including a condition known as peripheral artery disease (PAD) where
blood flow is blocked (often in the legs) and tissue
damage can occur.
Using mesenchymal-like stem cells derived from placenta,
Pluristem developed a
3D culturing system that allowed it to "tune" the cells
into producing a variety of cytokine cocktails that would facilitate repair in
a variety of
clinical conditions, including PAD.
Aberman draws a parallel with the wine industry: "Change how
you process grapes and you change the flavor
of the wine and its quality.
Likewise, if you change how you process the cells, you change how they function
and their quality," he says.
At the Biotechnology
Industry Organization's annual conference
in June, the company introduced the results of preclinical studies in the use
of the PLX system via
intramuscular (IM) injection rather than through
intravenous injection or direct application to the site of injury. According to
Aberman, the ability
to perform IM administration has significant market
implications that potentially broaden not only to what diseases the product can
be applied, but
also who can apply them and how often.
In July, the company announced a partnership with CPC
Clinical Research to initiate Phase II studies of the PLX system in PAD, but
perhaps
the most dramatic moment came back in May, when the company announced
the results of its compassionate use of PLX in a young girl who failed two bone
marrow transplants and was expected to die.
Within 10 days of the second and last injection of PLX, the
patient's hematological patterns
improved dramatically, and subsequent biopsies
showed that cells from both bone marrow transplants were finally growing and
maturing. After nine
months, the patient was discharged from the hospital and
is doing well.
"The physician treating the
girl was in the same hospital
where we had established our acute radiation models to develop PLX and he asked
for compassionate use," explains
Aberman. "You can do a lot in animals that may
not work in humans. This worked."
The rest of the story
Other areas for which cell-based
therapies are being
developed by these and other companies include: Autoimmune conditions such as
Crohn's disease and rheumatoid arthritis
(e.g., Osiris, TiGenix,
Mesoblast, TxCell); musculoskeletal conditions such as cartilage regeneration (e.g.,
Pluristem, Histogenics, Azellon Cell Therapeutics); ocular conditions such as
AMD and retinopathy (e.g.,International Stem Cell, EyeCyte, Advanced Cell
Technology); and oncological conditions such
as neutropenia (e.g., Cellerant
Therapeutics, Gamida
Cell Therapy Technologies).
Lessons learned?
Whether licking their wounds and dusting themselves off, or
learning from the lessons of others who have fallen
before them, the latest
crop of regenerative medicine companies and scientists seem to be taking a much
more methodical and deliberate approach to
developing the next generation of
cell-based therapies. It will take some time and patience, however, to see if
those lessons have become
ingrained. Code: E081230 Back |
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