Blazing the trail

Backed by strong venture capital funding, biotechs organize around promise of stem cell research

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A number ofbiotechnology firms dedicated to stem cells have been launched in the past fewyears, thanks to strong venture capital funding in geographic areas wheregovernment and science have favored stem cell research, according to Frost& Sullivan.
Notably,California ranks highest, with a total of 10 firms dedicated to all kinds ofstem cell research receiving either venture or IPO-backed funding. It'sinteresting to note that Geron Corp., which works with hESCs, has the maximummarket capital value at $605 million, despite the fact that adult stem cellresearch receives more funding.
Geron, locatedin Menlo Park, Calif., is considered by many to be the top biotechnologycompany in the field of stem cell research. Since its founding in 1990, Geronhas been granted more than 260 patents. The company has two anti-cancerproducts in human clinical trials. In 2009, Geron received FDA approval tobegin Phase I testing in humans of GRNOPC1, an eSC-based drug designed to treatspecific forms of spinal cord injury through remyelination of damaged axons.Geron also has several other embryonic stem cell treatments that are still inthe preclinical phase, including GRNCM1, a treatment for heart disease, andGRNIC1, a treatment for diabetes.
Here, we featurea handful of other companies that stand out as leaders in this market,according to Frost & Sullivan.

Company: AastromBiosciences Inc.


Ann Arbor, Mich.

Developing enhanced autologous cellular therapies for thetreatment of severe, chronic cardiovascular diseases
Borrowing itsname from its location—"Ann Arbor Stromal" was its first moniker—AastromBiosciences Inc. began as a device company but is now known as a developer ofprocess technologies and devices for cell therapy applications, including stemcell therapies and gene therapy.
Unlike some ofthe other companies operating in the same space, Aastrom manufacturers theautologous cells it uses in-house. A small quantity of bone marrow is takenfrom a patient's hip, and in a 12-day process, Aastrom expands the cellpopulations found in the extracted marrow. Then, in a single inpatientprocedure, the expanded mixed-cell therapy produced from this process—calledixmyelocel-T—is administered to the same patient to promote healing of theaffected tissues.
"We havedesigned our own highly automated, fully closed cell processing system,"explains Tim Mayleben, Aastrom's CEO, president and director. "It is the bestdevice in the world for processing autologous cells. And our success has beento think both strategically and medically about the kinds of diseases ourparticular technology is well-suited for."
Specifically,those are critical limb ischemia and dilated cardiomyopathy—criticalcardiovascular diseases that currently have limited or no treatment options.The company is in a Phase III clinical trial to study ixmyelocel-T patientswith critical limb ischemia and two Phase II clinical trials to study thetherapy in patients with dilated cardiomyopathy.
"These chronic,long-term, progressive diseases are well-suited to our technology," saysMayleben. "There are literally no treatment options for these patients, and ofthe options that are available—amputation, heart transplant, etc.—these arelimited in availability and expensive. Our vision at Aastrom is to get thefirst autologous cell therapy product in physicians' hands and used bypatients, so we can change the way that medicine is practiced. Our technologyalso has applications in other disease areas that we are just now starting toexplore."

Company: Advanced Cell Technology (ACT)

Santa Monica, Calif., and Marlborough,Mass.

Retinal degeneration; blood and cardiovascular diseases
Although ACT wasprincipally focused on hESCs, the company now also has some interesting workinvolving induced pluripotent stem (iPS) cells. ACT has three cellular productplatforms based on its stem cell technology—the first-ever proven alternativemethod for successful hESC generation without harm to the embryo, called the"single-cell blastomere" technique.
First, thecompany is focused on commercializing its hESC-based Retinal Pigment Epithelial(RPE) therapy for degenerative retinal disease, for which it recently initiatedtwo Phase I/II clinical trials. Retinal degeneration can cause a variety ofblinding diseases, including retinitis pigmentosa, Stargardt's disease(juvenile macular degeneration), age-related macular degeneration (AMD) andother degenerative diseases of the retina.
"One of thegreat things about working with the eye is that you don't have the immunerejection issues you would find in other parts of the body," says Gary Rabin,chairman and CEO of ACT.
ACT isparticularly focused on AMD, which afflicts more than 30 million peopleworldwide and is the leading cause of blindness in people aged 60 and older inthe United States. And as average life expectancy continues to rise, it ispredicted that the incidence of AMD will only continue to rise in tandem. DryAMD, the most prevalent form of the disease, represents a $25 billion to $30billion market in the United States and Europe alone, and there are currentlyno approved therapies available for this condition.
On July 14, ACTannounced the dosing of the first patients in each of its two Phase I/IIclinical trials for Stargardt's macular dystrophy and dry AMD using RPE cellsderived from hESCs. The patients were treated by Dr. Steven Schwartz, retinadivision chief at UCLA's Jules Stein Eye Institute. Both patients successfullyunderwent the outpatient transplantation surgeries and are recoveringuneventfully.
"It would begreat if the end result of these clinical trials is if we arrest the decline ofage-related macular degeneration," says Rabin. "The math works out readily tosee how this could be the largest drug therapy of all time—this could be biggerthan Lipitor."
ACT is alsodeveloping its hESC-based Hemangioblast (HG) platform for the treatment ofblood and cardiovascular diseases in a partnership with CHA Biotech of Korea.
Finally, the company is focused on advancing its Phase II-approved Myoblastautologous adult stem cell therapy for the treatment of chronic heart failure,advanced cardiac disease, myocardial infarction and ischemia.
ACT owns orlicenses more than 150 patents and patent applications related to stemcell therapy andregenerative medicine. The company also recently announced a collaboration withRoslin Cells for the storage and distribution of eSCs using ACT's Blastomeretechnology.

Company: Aldagen

Location: Research Triangle Park in Durham, N.C.
Employees: 16
Focus: Developing proprietary adult stem cell products for tissuerepair and regeneration, particularly in the cardiovascular market

When a companydecides to enter the stem cell research arena, it must make a very importantdecision: how and from where to derive the cells they will use. For Aldagen, aclinical-stage biopharmaceutical company developing proprietary regenerativecell therapies, that question served as the foundation for the formation of thecompany.
In 2002,Aldagen's founders took technology developed at Johns Hopkins University andDuke University and started a commercial enterprise. The technology identifies,selects and isolates specific adult stem cells that express high levels of theenzyme ALDH, which plays an important role in controlling the developmentalstate of stem and progenitor cells. It converts vitamin A into retinoic acids,which regulate genes and influence the differentiation of blood, neural, endothelialand other types of stem and progenitor cells.
Because Aldagenuses this technology to collect autologous cells from a patient's own bonemarrow, the risk of potential rejection of the injected cells in a patient isminimalized, says Edward L. Field, the company's chief operating officer.
"When youcompare us to other companies, we have a unique cell population that no oneelse has," Field says. "What we do is very different, but also very simple. Wedon't manipulate, culture or expand cells, so we are able to fairly rapidlyproduce and deliver them to the patient."
Compared to someof the other companies we are featuring here, Aldagen is fairly young, havingoperated for less than 10 years. Field attributes the company's youth to "thefact that a lot of us are trying to do what has never been done before."
"If you thinkabout commercializing new technology in our industry, it usually takes 20 to 25years from the seminal event to get commercial products to market, and stemcells are no different," he says.
Companies likeAldagen will be able to realize the promise of this groundbreaking research "ifwe can achieve the next milestone in stem cell research, which is putting PhaseIII studies and data sets on the table," says Field.
Aldagen isheaded in that direction, as it is beginning Phase II studies involvingtherapeutic candidates for critical limb ischemia and ischemic heart failure.Also, in May, the company—along with its collaborator, the Los Angeles Brainand Spine Institute (LABSI)—announced the enrollment of the first subject in aclinical trial that studies ALD-401, a unique stem cell population derived froma patient's own bone marrow, for the treatment of ischemic stroke.
"The strokemarket alone presents billion-dollar market opportunities," says Field,"because there are no therapeutic options or small-molecule drugs to treat it.In addition, our therapy is a regenerative, restorative kind of therapy thathas the potential to take costs out of the healthcare system by keepingpatients ambulatory. We have talked to payors, and they are very encouraging aswe move this program forward."

Company: Neuralstem Inc. 
Founded: 1996
Location: Rockville, Md., and San Diego; plans toopen subsidiary in China soon
Employees: 16

Focus: Using its patented neural stem cell technology to treatcentral nervous system diseases

In January 1992,attorney Richard Garr sat at the bedside of his four-year-old son Matt atChildren's Hospital in Washington, D.C., helplessly watching his difficultrecovery after an 18-hour procedure to remove a brain tumor.

Nearly 20 yearslater, Garr is the president and CEO of Neuralstem Inc., a publicly tradedbiotherapeutics company that is making headlines for its stem cell clinicaltrials to treat amyotrophic lateral sclerosis, (ALS, commonly known as LouGehrig's disease) and depression—and eventually, other diseases of the centralnervous system (CNS).

Bonded to thefather of one of his son's classmates, Dr. Karl Johe—a staff scientist at theLaboratory of Molecular Biology of the National Institute of NeurologicalDisease and Stroke—Garr saw an opportunity to alleviate Matt's suffering. In1996, he and Johe joined forces to commercialize Johe's Human Neural Stem Celltechnology.

The technologyallows for the isolation of CNS stem cells from tissue; the expansion, in vitro, of each cell up to abillion-billion times, or 60 doublings; and the controlled differentiation ofthe cells into mature, physiologically relevant human neurons and glia that canbe used to treat CNS diseases and conditions. This provides a unique window fortraditional drug discovery and genomic applications, Garr says.

"We screenagainst ourselves, and we screen against physiologically relevant human cells,so we can really see what's actually happening, which is predictive of whatwill happen in humans," he explains.

Neuralstem has14 patents to its name—issued all over the world—with more than 20 otherspending. The company's work with stem cells is evenly divided between usingthem to develop actual therapeutics and to screen against for drugs.
The companycurrently has two Phase I clinical trials underway.

The first is evaluating thesafety of Neuralstem's spinal cord stem cells in the treatment of ALS, andnotably, is the first ALS stem cell trial to be approved by the FDA. In June, Neuralstem announced that 12 patients beingtreated at Emory University in Atlanta safely received injections in the lumbarregion of the spine, prompting the trial's Safety Monitoring Board (SMB) tounanimously approve advancing the trial to transplantations in the cervicalregion. Neuralstem hopes these injections can help alleviate the breathing andswallowing difficulties that often lead to death in ALS patients.

Neuralstem'ssecond Phase I trial is testing NSI-189, the lead compound in the company'sneuroregenerative small-molecule drug platform, for the treatment of majordepression. Phase Ia is testing the drug in healthy volunteers for safety andtolerability.

Neuralstem hopesto conclude both trials within the next five years, and is preparing to do astroke trial in China. In fact, the company has several projects in the worksthat will give it a significant presence in Asia as well as the United States.

"We have afairly global ambition in terms of rolling out products and studies, and we'regrowing our infrastructure in that direction," says Garr.

Staking a claim
Growing stem cell market entices Big Pharmato harness its power for drug screening, toxicity testing
A roundup of North America's top fiveacademic research institutions in the stem cell arena


Tools of the trade

Life science tool providers provideconstant support to ever-evolving stem cell research community

To view all of the content from our three-part series onstem cell research, click here

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