Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
Through ups and downs, the question remains: Do induced pluripotent stem cells have near-term clinical potential?
Shinya Yamanaka of Kyoto University, Osaka, Japan, and John Gurdon of Gurdon Institute in Cambridge U.K., who once had a biology teacher tell him that his scientific ambitions were a “waste of time” shared a $1.2 million award as they won the Nobel Prize in Medicine earlier this month. The Nobel committee said the researchers had “revolutionized” science.
The two shared the prize for their discovery that “mature, specialized cells can be reprogrammed to become immature cells capable of developing into all tissues of the body,” according to the Nobel Assembly. “Their findings have revolutionized our understanding of how cells and organisms develop.”
And it was good to see good news about the hard work and progress in iPS cell research, given that the field has attracted its share of quackery. Most recently, Hisashi Moriguchi remarkably claimed that he had treated cardiac failure patients with iPS cells, personally hailing the procedure as a clinical breakthrough. But Moriguchi recanted earlier this month, admitting that for five of the six patients he was discussing “planned” procedures rather than actual events. “I guess I got a little bit high. That was wrong,” he explained. “I admit that I lied.”
Moriguchi claimed to have used a relatively minimalist combination of techniques to produce his cells, reporting that his method to reprogram cells used only microRNA-145 inhibitor and TGF-β ligand. But Hiromitsu Nakauchi, a stem cell researcher at the University of Tokyo, says that he has “never heard of success with that method” using a two-reagent only approach and said that he had also never heard of Moriguchi before the week of October 12.
According to a commentary published in Nature, Moriguchi’s feat would have “catapulted iPS cells into use in a wide range of clinical situations, years ahead of most specialists’ predictions”. “I hope this therapy is realized in Japan as soon as possible,” the head of a Tokyo-based organization devoted to helping children with heart problems told the Japanese newspaper Yomiuri Shimbun. Nature published its comments during the same week that Moriguchi presented his work at a meeting of the New York Stem Cell Foundation.
In most laboratories, multiple steps involving introduction of appropriate genes and culturing techniques are necessary to produce iPS cells.
After being alerted to Moriguchi’s story, Harvard Medical School and Massachusetts General Hospital (MGH), where Moriguchi said he performed the work, denied that the procedure had taken place. “No clinical trials related to Moriguchi’s work have been approved by institutional review boards at either Harvard University or MGH,” wrote David Cameron, a spokesman for Harvard Medical School in Boston. “The work he is reporting was not done at MGH,” says Ryan Donovan, a public-affairs official at MGH.
Producing iPS Cells
And producing iPS cells, in reality, is a lot more complex than Moriguchi would allow. “I know of no lab, despite huge efforts worldwide, that has yet succeeded in deriving iPS cells with chemicals alone,” says George Daley, M.D., Ph.D., of the Children’s Hospital Boston and Harvard Medical School, whose laboratory is developing methods for producing iPS cells as well as clinical applications for the technology, using techniques that involve considerable genetic manipulation.
iPS cells offer tremendous promise in treating difficult human diseases ranging from neurodenerative disorders to cancer because these cells can be formed from mature, differentiated body cells. This avoids sensitive issues involved using embryonic tissue for basic and clinical research. And these cells may also avert the need for immunosuppressive drugs as they can originate from a patient’s own mature cells.
But the current and near-term significant application for iPS cells may be their utility in understanding disease mechanisms and for drug screening, according to Nobel Laurate Dr. Yamanaka. He noted that while iPS cell technology may play a major role in regenerative therapy in the future, several issues must be overcome, including the “present low efficiency of iPS cell generation without genetic alterations, the possibility of tumor formation in vivo, and unregulated growth of the remaining cells that are partially reprogrammed and refractory to differentiation.”
These issues must be solved before iPS technology can be successfully used in clinical applications.
Dr. Daley agrees that, near-term, “the applications of these cells are in medically relevant basic research and drug discovery.” Dr. Daley said that looking at disease phenotypes in iSP cells derived from patients with, for example, Parkinson’s disease grown in cell culture offers “very valuable disease models and will be used as the basis for screening novel drugs.”
Dr. Daley says that closest at hand to potential treatments with cells are certain eye diseases, including retinitis pigmentosa and macular degeneration, as well as blood diseases. But, he says, “We remain remarkably ignorant about what it takes to turn cells into medicines.”
Dr. Daley and colleagues at the University of Iowa developed iPSCs generated from mouse dermal fibroblasts using retroviral transcription factors, intending to produce retinal precursor cells, and, ultimately, differentiated photoreceptorcells for retinal transplantation. These cells could, potentially, restore retinal function in animals with degenerative eye disease.
Following subretinal transplantation into degenerative hosts, differentiated iPSCs took up residence in the retinal outer nuclear layer and gave rise to increased electroretinal function as determined by ERG and functional anatomy. As such, adult fibroblast-derived iPSCs provide a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease, the investigators said.
iPierian of South San Francisco uses its knowledge and experience with developing iPS cells to discover drug targets for development of antibody-based therapeutics to treat neurodegenerative diseases.
The company builds disease models by reprogramming biopsy-derived fibroblasts from patients with neurodegenerative diseases, then reprograms the cells into iPSCs. These cells are then differentiated into functional disease-relevant cells including cortical neurons, motor neurons, microglia, and astrocytes. Grown together in petri dishes, pathophysiological and functionally differentiated disease models emerge.
“Technology is beginning to advance such that some researchers can now avoid the stem cell stage and go directly to a cell lineage such as a neuron,” Nancy Stagliano, Ph.D., CEO of iPierian, said. “The breadth of the field is driven by having an iPS cell that can be differentiated into multiple cells. The iPS cells serve as building blocks for forming a neuron, astrocyte, or microglial cell; each protocol for differentiation is different.”
“With neurodegenerative diseases,” she added, unlike diseases such as cancer, “it is difficult if not impossible to get samples while a patient is alive.” This has seriously hindered the development of disease-relevant models. But now, she said, “We can take fibroblasts from, for example, Alzheimer’s disease (AD) patients, and make them into a variety of brain cells.”
Having spent years at Ipierian getting the protocols for these models worked out, she says, “We have been excited in the changes and differences in cortical neurons from AD patients, compared to iPS cells from normal individuals.”
And, she noted, the company’s models have confirmed their lead drug candidate choices. “Our models in a dish exhibit significant changes in the amount and form of tau protein, confirming differences in the protein in AD models compared to normal neurons.” She further noted that the company has found a soluble form of the protein that makes an ideal drug target candidate.
Currently, she said, the company’s two programs, its anti-tau antibody program and complement protein program, “are entering animal studies. We are putting them into rat and mouse models of disease then we will be in the clinic in 2014 for both programs and hope to enter Phase I later that year.
“Our recent insights derived from human iPS cells have encouraged us to quickly move our Tau and Complement programs forward. iPierian’s patient-derived models of neurodegeneration and neuroinflammation are allowing us to realize the promise of iPSC technology in a very product-oriented way,” Dr. Stagliano noted.
While stem cells may not immediately provide therapies for human diseases, their use as models in drug discovery has given them an immediate purpose in life. As more models are developed that can accurately model neurodegenerative changes, more novel therapies may be discovered.
Patricia Fitzpatrick Dimond, Ph.D. (firstname.lastname@example.org), is a principal at BioInsight Consulting.