Menlo Park, Calif.-based Geron Corporation (GERN) said on July 5 it recently presented new data showing progress in developing stem cell-based therapies for the treatment of spinal cord injury, diabetes, heart attack damage, and bone fractures.
Geron scientists and collaborators presented data on four products it is developing from human embryonic stem cells (HESC):
– GRNOPC1, oligodendroglial progenitor cells for acute spinal cord injury
– GRNIC1, islet clusters for diabetes
– GRNCM1, cardiomyocytes for myocardial infarction
– Osteoprogenitor cells for bone fractures and osteoporosis.
The company said it also described advances in HESC culture and derivation techniques and further characterization of HESC-derived hepatocytes for liver failure and drug metabolism testing.
The data were presented at a meeting of the International Society for Stem Cell Research in Toronto.
“The progress sets Geron apart in terms of leveraging our human embryonic stem cell platform into the development of multiple therapeutic products,” said CEO Thomas Okarma. “Our most advanced product, GRNOPC1 for acute spinal cord injury, is in multiple IND-enabling studies. Its in vivo mechanism of action includes myelination and trophic support of damaged spinal cord neurons, resulting in significant locomotor recovery of spinal cord injured rodents. As our work progresses with other HESC-derived cell types such as cardiomyocytes, islets, hepatocytes and osteoprogenitor cells, we are hopeful that these cell types will also demonstrate significant, long-term regenerative capacity in animal models, setting the stage for clinical trials in patients.”
Data show that partial repair is observed in the spinal cord of injured rats transplanted with GRNOPC1, the company said.
Rats transplanted with the cells showed evidence of increased remyelination of axons and enhanced axonal survival and growth.
According to Geron, GRNOPC1 has been shown to secrete neurotrophic factors that can improve neuronal survival and stimulate axon growth.
And at least one known neurotrophic factor secreted by the cells, TGF-Beta2, has been identified that mediates this effect.
The company said that new studies presented by scientists at Geron and the University of California, Irvine, showed GRNOPC1 to stimulate axonal survival and growth both in tissue culture and in the rodent injured spinal cord.
Transplanted directly into the injury site of contused rats, the product induced 2.5 times more corticospinal tract neurons near the lesion site compared to controls.
“The data suggest that GRNOPC1 may not only prevent death of injured neurons, but could restimulate growth of axons in the lesion area, potentially allowing new pathways for nerve conduction past the injury,” the company said.
Significant progress has been made in identifying the factors produced by GRNOPC1 that may be responsible for these effects on axonal survival and growth.
Conditioned medium produced by GRNOPC1 cultures was found to contain neurotrophic factors that significantly increased neuronal survival and axonal growth in vitro.
The axonal growth stimulating activity of GRNOPC1 was characterized at the molecular level and shown to result in part from secretion of TGF-Beta2 protein, a known neurotrophic factor.
The trophic effects were partially inhibited by a neutralizing TGF-Beta2 antibody, suggesting that GRNOPC1 secretes other additional neurotrophic factors as well.
“These studies show that GRNOPC1 impacts two of the major defects that occur at the spinal cord injury site,” said Jane S. Lebkowski, senior vice president of regenerative medicine. “In addition to inducing remyelination, GRNOPC1 produces neurotrophic factors that reduce deterioration of axons and stimulate their partial regrowth, potentially enabling development of alternative circuitry through the lesion site.”
The company also offered data showing the feasibility of scalable production of GRNOPC1 from its master cell bank (MCB) of H1 HESCs, as well as the long-term survival of GRNOPC1 made from the MCB after transplantation into the rodent injured spinal cord.
Geron scientists presented data on the production of GRNOPC1 under current good manufacturing practices (cGMP) from its Master Cell Bank (MCB) of pathogen-free H1 HESCs.
Data also showed that human immune cells have little direct immunoreactivity with GRNOPC1.
This suggests that temporary, low-dose immune suppression should enable transplanted GRNOPC1 to survive without immune rejection.
When the injury heals, the transplanted cells should be protected by the blood-brain barrier, allowing immunosuppression to be withdrawn.
Dr. Anish Majumdar, Geron’s senior director of cell therapy research, presented details on the production, enrichment, and characterization of HESC-derived Islet Clusters (GRNIC1) for use in treating diabetes.
The GRNIC1 production procedure generates pancreatic endocrine cell clusters that express pancreatic islet transcription factors as well as the hormones insulin, glucagon and somatostatin in physiological proportions.
Majumdar showed that these clusters have biochemical and physical attributes of islets, budding off as discrete cell aggregates that can be enriched by simple size exclusion.
Previous studies have shown that transplantation of GRNIC1 can positively impact survival in rodent models of diabetes and produces measurable levels of human insulin in the animals’ blood.
Other studies provided evidence that Geron’s method of producing ventricular cardiomyocytes (GRNCM1) can be scaled, and can yield cells that can be cryopreserved and thawed.
The method generates ventricular cardiomyocytes that display appropriate gene expression patterns and responsiveness to cardiac drugs, as well as engraft and survive in the damaged zone of an infarcted rodent heart, providing the rationale for their use to treat infarct-induced heart failure, according to the company.
A new method to scalably produce cardiomyocytes was described in two presentations by Dr. Joseph Gold, director of stem cell biology, and other Geron scientists.
Geron said the method has several advantages over previous methods: it uses serum-free media and a novel combination of defined growth factors, does not require embryoid body formation or co-culture with other cell types, directly generates populations of cardiomyocytes at up to 80 percent purity without further purification, and produces yields of cardiomyocytes sufficient for large animal and eventually human use.
These GRNCM1 cells spontaneously contract, express appropriate cardiomyocyte transcription factors, respond normally to cardiac drugs, have normal electrophysiological properties and can be cryopreserved and thawed with high viability.
The new production method enables the scalable manufacturing of cardiomyocytes for use in preclinical testing in large animal models of myocardial infarction and heart failure.
It can be used successfully with undifferentiated HESCs maintained without feeder cells or fibroblast conditioned medium, resulting in a production process that can be scaled and performed under cGMP conditions.
When transplanted into the infarct zone of infarcted nude rats, these cardiomyocytes engrafted and survived, the company said.
All animals had robust human cardiac grafts at four weeks after transplant, surviving in the face of the ischemic and reperfusion injury induced by coronary artery ligation and release.
In another presentation by Geron collaborators from the Imperial College of London, HESC-derived cardiomyocytes were configured into a drug screening assay that measures contractile frequency and amplitude changes in response to various cardioactive drugs.
Geron scientists and collaborators at the Roslin Institute and CXR Biosciences in Scotland presented a study showing the functionality of HESC-derived hepatocytes that could alter the landscape of pharmaceutical drug discovery by defining early in drug development the toxicity and hepatic metabolism of new drugs before they enter expensive clinical trials.
The company said the cells may find use for both extra-corporeal liver assist devices to treat acute hepatic failure as well as transplantation to restore hepatic function in vivo.
In another presentation, Geron collaborators at the Medical School, University of Edinburgh, and the Roslin Institute in Scotland reported on methods to generate osteoprogenitor (bone-forming) cells from both HESCs and bone marrow-derived mesenchymal stem cells (MSCs).
They compared the capacity of the two cell types of bone-forming cells to repair a full thickness, critical size calvarial defect generated in rats.
According to the company, results showed significantly more bone formation in vivo in rats receiving HESC-derived osteoprogenitors compared to those receiving MSC-derived osteoprogenitors.
The HESC-derived cells were detected throughout the calvarial defect and were highly integrated into the matrix carrier used to deliver the cells to the lesion.
Contact: David L. Greenwood, 650-473-7765, http://www.geron.com.
