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A body of work
The longtime goal of regenerative medicine has been todiscover ways to either replace endogenous tissue functions with exogenouscells, or to at least give the body an opportunity to heal itself through thestimulation and support of endogenous repair functions. Thus, stem cell-basedtherapies have been developed that target an array of conditions.
One area that has proven to be a success story for regenerativemedicine has been wound healing, although much of the earlier efforts werefocused on the cell-based engineering of skin replacements. Companies likeOrganogenesis, based in Canton, Mass., continue to pioneer the field of skinreplacement—in this case, with its Apligraf technology, which is essentiallyskin grown in a Petri dish.
Similarly, Columbia, Md.-based Osiris Therapeutics hasleveraged its growing expertise in stem cell technologies to develop Grafixskin replacement technology, whereby MSCs are cultured with growth factors anda natural scaffold known as an extracellular matrix to form newly generatedskin.
MacroCure took a slightly different route, however, when itdeveloped its CureXcell technology, which is currently on the market in Israel.Rather than produce a skin replacement, MacroCure developed a cell-basedtherapy that stimulates cells within the wound to initiate its own repair.
"We like to think of skin substitutes such as Apligraf ashealing from the outside in, whereas CureXcell is more about healing from theinside out," explains Mashiach. "CureXcell is a full, systemic approach using acocktail of cells harvested from whole blood, which are injected into the woundand trigger a cascade of cellular functions that promote angiogenesis and theformation of new collagen."
In CureXcell, the cells are activated to maintain their potencybefore being injected into the wound tissue, where they trigger a cascade thatfirst re-establishes hemostasis, then inhibits inflammation, promotesrevascularization of the tissues and finally stimulates collagen production andwound healing.
"We're currently enrolling patients in a Phase III study inthe United States with a commitment from the FDA to speed the product toapproval if it meets its clinical criteria, and CureXcell has been tested inmore than 5,000 patients in Israel on a variety of wound types," says Mashiach.
Nerves of steel
Another area of intense interest and significant unmetmedical 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 theNurOwn system to target conditions such as ALS, PD and multiple sclerosis. MSCsfrom a patient's bone marrow are induced to produce neurotrophic factors. Thesecells are then transplanted back into the patient near the site of damage,where they stimulate local neuronal growth and hopefully slow or stop damageprogression.
According to company CEO Adrian Hurel, the company iscurrently conducting Phase I/II safety studies in Israel in patients with bothlate- and early-stage ALS, and recently entered into a memorandum ofunderstanding with institutes in Massachusetts to conduct Phase II ALS studiesthey hope to initiate in late 2012.
In the United Kingdom, meanwhile, ReNeuron recentlyinitiated clinical testing (the Pilot Investigation of Stem Cells in Stroke, orPISCES, study) of its allogeneic neural stem cell technology in patientsdisabled by stroke. Starting with a fetal progenitor source back in 2003, thecompany screened a variety of immortalized cell lines to identify potentialtherapeutic candidates, cells targeting stroke-related damage being thestrongest initial candidate.
In a June release describing early data from the firstpatients in the PISCES study, principal investigator and neuroscientist KeithMuir of the University of Glasgow said, "The data indicate that the ReN001 treatment has a good safety profile atthe doses administered thus far. The preliminary signals of potentialfunctional benefit, whilst intriguing, will require further investigation in asuitably designed Phase II efficacy study."
At its heart
Given the increasingly aging population coping withconditions such as obesity and cardiovascular disease, this disease area hasbecome a target for intensive research in stem cell-based therapies.
In July, Los Angeles-based Capricor announced it hadreceived FDA approval to initiate the Phase II ALLSTAR clinical trial of itsIntensicor system in patients following large myocardial infarctions (MIs).With Intensicor, cardiac-derived stem cells (CDCs) are cultured from donorhearts that could not be used for transplantation (allogeneic) or biopsiedheart tissue from the patient (autologous), and then reinjected into thedamaged heart muscle to stimulate cardiac regeneration.
In a similar manner, Cleveland's Athersys has developed theMultiStem system to treat damage following MI, as well as other conditions.MultiStem relies on allogeneic stem cells isolated from bone marrow or othernon-embryonic tissues that are introduced to ischemic regions of the heart througha catheter. The company's Phase I study, published earlier this year, showedsignificant improvement in cardiac function following MI without any safetyconcerns.
Cardiovascular disease doesn't just impact the heart,however, as events involving the heart can have significant impact elsewhere inthe body, such as the kidneys. As described by Brenner, cardiac interventionssuch as the use of specific contrast agents or bypass machinery can triggeracute kidney injury (AKI).
Using MSCs derived from allogeneic bone marrow, AlloCureinduces the cells to secrete a variety of growth factors and anti-inflammatoryfactors upon introduction to the damaged tissue, triggering repair through thegrowth of new cells and blood vessels. In November, the company presentedfindings of a Phase I safety and efficacy trial, showing that treatment notonly lowered the incidence of AKI in cardiac surgery patients, but alsoshortened hospital stays and reduced hospital readmission rates. A Phase IIstudy was underway as we went to press, with results from more than 200patients expected in early 2014.
The so-called obesity epidemic has also triggered a growingproblem—at least in the developed world—of diabetes, an area that is activelybeing explored by a number of companies.
Type 1 diabetes is an autoimmune disease in which theinsulin-producing cells in the pancreas are specifically attacked anddestroyed. The autoimmune aspect of the condition complicates its treatment, explainsSarah Ferber, chief scientific officer and founder of White Plains, N.Y.-basedOrgenesis, as any healthy pancreatic cells introduced into the body wouldsimply be destroyed.
For this reason, Orgenesis focused its efforts on theconversion of autologous liver cells into insulin-producing cells that could bereimplanted in the liver to essentially replace the missing functions of thepancreas.
"Liver is developmentally related to the pancreas and bothtissues are sensitive to glucose," she explains. "In addition, liver has a substantialregenerative 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 andworms), Ferber explains, do not have a separate liver and pancreas, but rathera single organ called the hepatopancreas.
The company is still in the preclinical proof-of-conceptphase, but has initiated conversations with regulators about proceeding toclinical trial.
Like cardiac disease, diabetes does not simply limit itseffects to the blood sugar and energy levels, but can also have secondaryimpacts, including a condition known as peripheral artery disease (PAD) whereblood 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 cellsinto producing a variety of cytokine cocktails that would facilitate repair ina variety of clinical conditions, including PAD.
Aberman draws a parallel with the wine industry: "Change howyou 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 functionand their quality," he says.
At the Biotechnology Industry Organization's annual conferencein June, the company introduced the results of preclinical studies in the useof the PLX system via intramuscular (IM) injection rather than throughintravenous injection or direct application to the site of injury. According toAberman, the ability to perform IM administration has significant marketimplications that potentially broaden not only to what diseases the product canbe applied, but also who can apply them and how often.
In July, the company announced a partnership with CPCClinical Research to initiate Phase II studies of the PLX system in PAD, butperhaps the most dramatic moment came back in May, when the company announcedthe results of its compassionate use of PLX in a young girl who failed two bonemarrow transplants and was expected to die.
Within 10 days of the second and last injection of PLX, thepatient's hematological patterns improved dramatically, and subsequent biopsiesshowed that cells from both bone marrow transplants were finally growing andmaturing. After nine months, the patient was discharged from the hospital andis doing well.
"The physician treating the girl was in the same hospitalwhere we had established our acute radiation models to develop PLX and he askedfor compassionate use," explains Aberman. "You can do a lot in animals that maynot work in humans. This worked."
The rest of the story
Other areas for which cell-based therapies are beingdeveloped by these and other companies include: Autoimmune conditions such asCrohn'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 asAMD and retinopathy (e.g.,International Stem Cell, EyeCyte, Advanced Cell Technology); and oncological conditions suchas neutropenia (e.g., CellerantTherapeutics, Gamida Cell Therapy Technologies).
Whether licking their wounds and dusting themselves off, orlearning from the lessons of others who have fallen before them, the latestcrop of regenerative medicine companies and scientists seem to be taking a muchmore methodical and deliberate approach to developing the next generation ofcell-based therapies. It will take some time and patience, however, to see ifthose lessons have become ingrained.