iPS Cell Production
GEN asked CDI vp and chief commercial officer Chris Parker about CDI’s approach to iPS cell production, as well as pharma’s acceptance of iPSC-derived human cell models of disease states.
“The relatively easy question for us to answer is whether you can make cells that represent a portion of the brain from a patient with neurodegenerative diseases,” he explained. But, he noted, the key question was whether you can generate them in sufficient quantity to be useful in a drug development environment. “We can create inventory of neurons sufficient to allow large-scale screening endeavors.” He further commented that “the therapy won’t come from a thimbleful of cells from a diseased patient, but from a vat.”
“We consistently produce these cells in large enough quantities such that pharma companies can build infrastructure around them. For CNS discovery, we produce forebrain neurons and will shortly provide dopaminergic neurons as well.”
Parker noted that some companies that were getting out of CNS research because of the lack of valid models for neurodegenerative disease are reinvigorating their studies. This is because, “for the first time, iPSC-derived neurons are available from patients in the quality, quantity, and purity required by pharma to represent those diseases,” he said.
He noted that the company has made a tremendous investment in the technology and infrastructure to industrially produce these iPS-based cell models in quantities sufficient to support drug development enterprises. For example, he says, a particular challenge is maintaining supplies for making the cells that “some manufacturers have never produced before, and a consistent supply is critical.”
Parker further notes that the company has developed numerous collaborations that will allow it to obtain cell samples for generation of iPS cells from different patients with the same disease and make panels of those neurons in quantity.
“The difference is going to be in the donor—can the disease be manifested in the dish based on its etiology, latency, and underlying cause? Our experience has shown that either through creation of a diseased patient’s iPS-derived cells or through manipulation of a healthy iPSC-derived human cell to mimic a disease state, the ability is there to study the disease in a dish,” he said.
Significant government support focuses on studying iPS cell-based models to support drug development and other basic research for these diseases. In 2009, the National Institute of Neurological Disorders and Stroke (NINDS) funded three consortia to develop iPS cell lines from individuals with Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). By generating these cells to become specialized types of neurons, researchers hope to determine and examine how these neurons die in each disease as well as test drugs that may slow or prevent neuronal death.
And many teams of scientists are racing to create disease models in a dish for neurodegenerative disorders. Last June in the journal Cell Stem Cell, an international team of researchers from several institutions, including UCSF’s Gladstone Institute, working as part of the HD iPSC consortium, reported that they had generated and characterized 14 iPSC lines from HD patients and from individuals without the disease.
Microarray profiling of the iPS cells, the investigators said, showed the CAG-repeat expansion association gene expression patterns that distinguish HD patient-derived cell lines from controls, and early-onset vs. late-onset HD. Further, the differentiated HD neural cells showed disease-associated changes in electrophysiology, metabolism, cell adhesion, and, ultimately, cell death for lines with both medium and longer CAG-repeat expansions.
The longer repeat lines were, however, the most vulnerable to cellular stressors and BDNF withdrawal, as assessed using a range of assays across consortium laboratories.
This HD iPSC collection, the authors concluded, represents a resource to elucidate disease mechanisms in HD and provides a human stem cell platform for screening new candidate therapeutics.
“The track record of animal models for predicting therapies that will work in people has been poor, making drug discovery for neurodegenerative diseases very costly—and therefore less attractive to drug companies. We hope to change that,” said Gladstone senior investigator Steve Finkbeiner, M.D., Ph.D.
But other investigators note that plenty of challenges remain before enshrining iPS cells as a true reflection of human disease states. Although, they said, seeing expected disease phenotypes in differentiated cells from patient-derived iPSCs is “encouraging”, the next challenge will be discovering phenotypes in complex or idiopathic diseases including amyotrophic lateral sclerosis or AD or type 2 diabetes.
Nonetheless, as noted by Dimos et al., in their review of iPS cell technology, patient-derived iPS cells may prove highly complementary to current drug discovery methodologies, particularly high-throughput human pharmacology applications.