Stem cell research advances in fits and starts

ACT's patented single-cell blastomere technology generates human embryonic stem cells (hESCs) for clinical testing and trials--image courtesy of Advanced Cell Technology

When Osiris Therapeutics ($OSIR) won Canadian regulatory approval recently for Prochymal as the world's first off-the-shelf stem cell treatment, company president and CEO C. Randal Mills said the advance after so many ups and downs felt like he had finally achieved "first-generation time travel."

It is true, the product made with mesenchymal stem cells from adult donors to treat graft-versus-host disease (GvHD) in children represents a genuine victory in a spotty history for the field. Osiris' advance comes 20 years after stem cell research seemed poised to change the world with the possibility of curing a wide range of diseases. But researchers have struggled in fits and starts in the face of scientific and political obstacles.

What's different now? Stem cell research continues morphing into new areas. Stem cells were once theorized to be a therapy in and of itself--a way to directly treat diseases or restore people's health from debilitating conditions. But scientists are now exploring how to use the cells indirectly to generate tissue or immune responses that can achieve the same goals. Scientists, for example, are increasingly using pluripotent stem cells from different parts of the body that can be tested as treatments, drug therapy targets or as ways to build models of disease on which to test drugs for toxicities. And they offer some of the advantages of embryonic stem cells without the political baggage.

The field today is well beyond whether to use embryonic or adult stem cells, a choice that became highly politicized in recent years as U.S. government leaders debated the ethics of using stem cells taken from embryos.

Interestingly, the number of ongoing stem cell-related clinical trials appears to be growing, reflecting the renewed focus on translating discoveries into therapies. In 2000, for example, reported 95 stem cell-related trials in Phase I or Phase II. In 2010, that number jumped to 306. The number grew again in 2011 to 324 stem cell-related studies in either Phase I or Phase II trials.

David Scadden--image courtesy of David Scadden

"The field has matured, and it is still young," says David Scadden, co-director of the Harvard Stem Cell Institute and director of the Center for Regenerative Medicine at Massachusetts General Hospital.

Defeat and progress

The field is hardly a bad luck option. Despite setbacks, for example, Osiris made history with Prochymal. But that boost follows some major lows. In November, Geron ($GERN) halted development of its Phase I stem cell trial for spinal injury, after which the company subsequently gave up on embryonic stem cell research and announced that it would sell its program. Recently, in another setback, South San Francisco-based iPierian also stepped away from stem cell research. The company said it will use its expertise in developing disease models using induced pluripotent stem cells to instead focus on discovering antibodies that fight neurodegenerative disease.

But both preclinical and clinical trials have also generated some promising news in recent months.

On the preclinical side, researchers at the University of Minnesota successfully morphed pluripotent stem cells grown from skin, in mice, into various muscle-forming cells, treating their version of muscular dystrophy. Other findings have run the gamut: Genetically modified human blood stem cells helped hold HIV at bay in preclinical trials at the University of California-Davis; Swedish scientists identified stem cells in the brain that help form new brain material; and Columbia University researchers used human bone marrow stem cells to re-create a single person's immune system in a mouse. University College London scientists chemically altered healthy stem cells from human eyes into retinal ganglion cells and then used them to help improve the sight of glaucoma-stricken rats.

On the side of human testing, Advanced Cell Technology ($ACTC.OB) remains the only company with therapies in human clinical trials using human embryonic stem cells (hESC). The company is running a Phase I/II clinical trial to treat dry age-related macular degeneration and a Phase I/II trial to test hESC-derived retinal cells to treat patients with the eye disease Stargardt's Macular Dystrophy.

Gary Rabin, the CEO of ACT, remains bullish, referring to stem cell and gene therapy as "the future of medicine."

In December, StemCells ($STEM) announced that its first set of patients with chronic spinal injury were transplanted with the company's human central nervous system stem cells (HuCNS-SC). Interim results from the trial show that the treatment has been well tolerated, the company said. StemCells has also begun recruiting patients from the U.S. and Canada.

Neuralstem ($CUR) began the first FDA-approved stem cell trial for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, at Emory University in 2010. Neuralstem seeks to treat symptoms of ALS using transplantation of the company's human spinal cord stem cells (HSSCs) directly into the patient's spinal cord's grey matter. In March, it announced that a second patient had received the transplantation in the upper back; the previous cohort of patients had been treated in the lower back region only.

There are also several institutions and companies using mesenchymal stem cells in human trials: Mesoblast is conducting a Phase II study for Type 2 diabetes, and partners CytoMed and Beike are using umbilical-cord derived mesenchymal stem cells in a Phase II study to treat lupus nephritis. Additionally, China's State Food and Drug Administration has green-lighted a Phase II trial using umbilical cord-derived mesenchymal stem cells in the treatment of ALS; the trial will involve therapy with the cells by lumbar puncture.

And in academic clinical trials, scientists at the University of Louisville in Kentucky and Northwestern Memorial Hospital in Chicago helped 5 patients with kidney transplants wean themselves off their organ rejection drugs by using organ donor blood stem cells. Massachusetts General Hospital researchers led efforts to use stem cells from a woman's ovaries to morph them into functional eggs, both in a lab dish and with mice. The researchers have helped form a startup called OvaScience to commercialize their findings. In another case, researchers helped slow the progression of kidney disease using stem cells derived from amniotic fluid.

Incremental advances

Not everyone sees stem cell research as having made broad strides. Dr. Joseph Antin, chief of stem cell transplantation at Dana-Farber Cancer Institute in Boston and professor of medicine at Harvard Medical School, says the progress has been more limited, with steady progress through the use of embryonic stem cells and induced pluripotent stem cells--where "the idea was that you can take a cell or skin cell and do something to it and make it revert to more primitive cells."

Those advances, Antin said, have been slow and steady rather than dramatic, such as incremental advances in gene therapy for blood disorders--taking pluripotent stem cells and transplanting them to treat inherited disorders of the metabolism or immune system.

"Very few (advances) come down to lightning bolts," he said. "I would characterize most going on in the stem cell area as incremental."

But Scadden says even the heightened focus on reprogramming pluripotent stem cells to treat various conditions is significant.

"There has been an increased appreciation for both the potential of reprogramming and, frankly, some of its limitations," he said. "We have learned a lot about how reprogramming back to an embryonic pluripotent state is something that can be done quite readily. But unfortunately, some recent studies have indicated that cells created have a number of genetic alterations that would raise concern about using them in the clinic."

Funding challenges

Despite clinical advances in the field, all of that is for nothing without the cash to fuel the science forward. C. Randal Mills, Osiris Therapeutics' CEO, acknowledges that the capital markets are much tighter for life sciences companies after the 2008 economic crash. But, he said, "Good ideas still do get funded."

Mills sees ideas that aren't overly complex as likely to still get investor attention, and notes that partnerships with larger pharmaceutical and medical device companies provide viable funding options. More complex concepts, however, such as blending stem cell research with gene therapy, are harder sells right now, he believes.

"When you start proposing mixing stem cells with gene therapy you are in second-generation time travel," he said. "It is hard to put money down for (these) because the road is so long and uncertain."

Mills is on the review committee for the California Institute for Regenerative Medicine, which is distributing a $3 billion state stem cell research fund. He points out that state funds such as this are a viable option for non-dilutive research funding, as are federal grants from the National Institutes of Health, at least under the Obama administration.

"The NIH is back open for business," he said.

Douglas Cole, a partner at Flagship Ventures in Cambridge, MA, sees "limited venture funding" available for stem cell research startups. He said stem cell treatments that are ready for commercial applications would be the most likely to win financing. But there's the catch: Most treatments are years away from the commercial marketplace, assuming they pass all of their clinical and regulatory hurdles.

Moving forward, he said, stem cell companies will gain funding if they have "enough depth of biological understanding to give a clear direction forward and have developed therapies." Also, he said, companies must have a clear sense of what therapeutic modalities will be best suited to their approaches. And treatment developers will have to solve plenty of issues, such as insuring how to make the treatments at a viable cost so they are safe and provide reliable dosing. But in the near term, Cole sees stem cell work remaining largely at the research stage rather than the commercial one.

"As a general statement," he said, "it is still early."

Jennifer Levin contributed research and reporting to this article.