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SPECIAL REPORT: Regenerating interest in stem cell medicine (PART 2)
TO SEE PART 1 OF THIS STORY, CLICK HERE.
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.
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).
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.