Spotlight on Stem Cells
A look at some recent stem cell-related R&D news and an update on the most notable stem cell research meeting of the year.
ISSCR 2020: Hold the dates but pass on the plane ticket
Annual stem cell meeting is going virtual this year due to the ongoing COVID-19 pandemic
By Jeffrey Bouley
We have already seen many annual meetings this year—including ones that we typically preview here in the pages of DDNews—get canceled, delayed indefinitely or turned into virtual events. And on the stem cell research front, the ISSCR annual meeting put on by the International Society of Stem Cell Research (ISSCR) falls in that third category.
ISSCR still describes it as a meeting that “gathers the world’s leading scientists, clinicians, business leaders, ethicists and educators from more than 65 countries,” adding that “Together, we represent the full spectrum of stem cell science and regenerative medicine. Discovery, new business, careers, advocacy and relationships start here.”
But this year, now that we have ISSCR 2020 Virtual, they just won’t be happening face to face.
As the ISSCR noted in a news release on April 14, you should still hold the dates of June 24-27—you just shouldn’t be planning on heading to Boston anymore. As of the end of April, when this issue went to press, details about the virtual event were still forthcoming online, so keep checking in at the ISSCR website at www.isscr.org until those details show up if you’re interested in the event.
“The Society remains committed to creating exceptional opportunities to share, discuss and present new science in the stem cell field,” said Deepak Srivastava, ISSCR’s president. “Transforming the in-person meeting to a virtual platform allows our field to share new discoveries and engage in vital conversations that will advance our field and fulfills the mission of the Society.”
Founded in 2002, the ISSCR bills itself as the leading professional organization of stem cell scientists, representing more than 4,000 members across 67 countries. Members hail from industry to academia and everywhere in between, and the organization’s mission is to focus on the responsible advancement of stem cell research and its translation to the clinic.
In the interests of keeping the stem cell theme going for this issue even in the absence of a show preview feature, continue below for recent news of discovery and development in this research area.
COPD as a lung stem cell disease
Researchers say that single cell cloning tells the story of abnormal cells
HOUSTON—Two internationally renowned stem cell experts say that they have found an abundance of abnormal stem cells in the lungs of patients who suffer from chronic obstructive pulmonary disease (COPD), a leading cause of death worldwide.
Specifically, Dr. Frank McKeon, a professor of biology and biochemistry at the University of Houston and director of its Stem Cell Center, and Dr. Wa Xian, research associate professor at the center, used single cell cloning of lung stem cells to make their discovery—and now they are targeting the cells for new therapeutics.
“We actually found that three variant cells in all COPD patients drive all the key features of the disease. One produces tremendous amounts of mucins which block the small airways, while the other two drive fibrosis and inflammation which together degrade the function of the lung,” Xian reported in the May 14 issue of the journal Cell. “These patients have normal stem cells, though not many of them, but they are dominated by the three variant cells that together make up the disease.”
COPD is a progressive inflammatory disease of the lungs marked by chronic bronchitis, small airway occlusion, inflammation, fibrosis and destruction of alveoli, which are tiny air sacs in the lungs which exchange oxygen and carbon dioxide molecules in the blood. The Global Burden of Disease Study reported 251 million cases of COPD worldwide in 2016.
Despite being one of the biggest causes of death on the planet, relatively little has been written or understood about the root cause of COPD, the researchers note. Over the past decade, Xian and McKeon developed technology for cloning stem cells of the lungs and airways, noting that different parts of the airways give different stem cells, related but distinguishable.
“It’s quite remarkable,” said McKeon. “In the deep lung, the distal airway stem cells gave rise to both the distal tubes and the alveoli and our research indicates those are the stem cells that make it possible for lungs to regenerate on their own.”
Xian and McKeon discovered lung regeneration in 2011 in their studies of subjects recovering from infections by an H1N1 influenza virus, which was nearly identical to that which sparked the 1918 flu pandemic.
The pair found that, in contrast to normal lungs, COPD lungs were inundated by three unusual variant lung stem cells that are committed to form metaplastic lesions. These lesions are known to inhabit COPD lungs, but are seen by many as a secondary effect without a causal link to the pathology of COPD.
After the team’s postdoctoral fellow, Wei Rao, transplanted each of the COPD clones into immunodeficient subjects, the team found they not only gave rise to the distinct metaplastic lesions of COPD, but they separately triggered the triad of pathologies of COPD, including mucus hypersecretion, fibrosis and chronic inflammation.
“The long-overlooked metaplastic lesions in COPD were, in fact, driving the disease rather than merely secondary consequences of the condition,” noted McKeon.
Now that the team knows the identity of the cells that cause inflammation, fibrosis and small airway obstruction, they are hard at work screening them against libraries of drug-like molecules to discover new therapeutics.
“As we now know the specific cells responsible for COPD pathology, we can target them, much as we would cancer, with specific drugs that selectively kill them off and leave the normal cells to regenerate normal lung tissue,” said Xian.
Stem cell combo therapy could bring relief for gastroparesis
DURHAM, N.C.—A new study released recently in STEM CELLS Translational Medicine, “Functional Restoration of Ex-vivo Model of Pylorus: Co-injection of Neural-Progenitor Cells and Interstitial Cells of Cajal,” could provide a major breakthrough in finding a cure for gastroparesis, a painful condition in which the stomach is unable to empty itself of food.
The study, led by Drs. Prabhash Dadhich and Khalil N Bitar at the Wake Forest School of Medicine, shows how transplanting neural stem cells in combination with interstitial cells of Cajal (ICCs) can restore the stomach muscles’ function and enable food to once again move normally through the digestive system.
As Bitar explained, “ICCs are the ‘pacemakers of the gut.’ Neurons relax smooth muscle with help of ICCs. A reduction in both these types of cells in the stomach negatively impacts the activity and endurance of its smooth muscle cells, which are needed to push food into the small intestine. This inefficiency can lead to gastroparesis.”
“Current treatments—mainly medications, a change of diet and, in some cases, surgery—are all palliative solutions. They don’t bring long-term relief. However, several recent studies have shown the promise of transplantation of various stem cells and progenitor cells as an effective, long-term solution to this condition,” he added.
While different studies have reported survival and functional differentiation of various stem cells/progenitor cells in the embryonic gut or post-natal colon, they involved transplantation of neural stem cells or embryonic neural crest cells, not adult enteric neural progenitor cells (NPCs).
“We didn’t know whether enteric nervous system (ENS)-derived adult neural-progenitor cells (NPCs) could migrate, proliferate and generate functional neurons in the postnatal pylorus,” Dadhich said. “ICCs are another critical factor in neuromuscular dysfunction and essential for long-term restoration of the neuronal functionality of the pylorus. So in our study, we investigated how transplanting both cell types together would affect a dysfunctional pylorus.”
To this end, ICCs and enteric NPCs were isolated from rat duodenum and treated with fluorescent proteins, tagging them for tracking. Rat pylorus was harvested, and an ex-vivo neuromuscular-dysfunctional pylorus model was developed by selective ablation of the neurons and ICCs in the pyloric sphincter.
The ENS-derived NPCs and the ICCs were then simultaneously injected into this model of dysfunctional pylorus. The results showed that this combo approach did indeed help the injected cells survive and integrate with host muscle layers, just as the researchers anticipated.
“Our analysis also confirmed the reinstatement and restoration of the stomach muscles’ functionality, both of which are critical in the treatment of pylorus dysfunctionality,” Bitar remarked. “These findings are very promising. We hope this study opens avenues for future cell-based clinical applications.”
FDA authorizes two Athersys trials of MultiStem
One focuses on COVID patients with ARDS and the other looks at trauma
CLEVELAND—Athersys Inc. announced April 13 that the U.S. Food and Drug Administration (FDA) had authorized the company to initiate a Phase 2/3 pivotal study to assess the safety and efficacy of the MultiStem stem cell therapy in subjects with moderate to severe acute respiratory distress syndrome (ARDS) induced by the novel coronavirus disease (COVID-19).
This program falls under the current Investigational New Drug (IND) application for the company’s completed MUST-ARDS study, and as such, a new IND does not need to be filed, Athersys noted.
The primary efficacy endpoint will be number of ventilator-free days through day 28 as compared to placebo, a well-established endpoint for ARDS trials that evaluates an intervention’s combined impact on survival and liberation from invasive mechanical ventilation. The secondary objectives of this study are to evaluate pulmonary function, all-cause mortality, tolerability and quality of life among survivors associated with MultiStem therapy as a treatment for subjects with moderate-to-severe ARDS due to COVID-19.
“We are grateful for the FDA’s timely review and feedback during our design of this pivotal Phase 2/3 study,” said Dr. Eric Jenkins, senior medical director and head of clinical operations at Athersys. “With encouraging nonclinical and clinical data, affirmed by the FDA’s Fast Track designation for ARDS, Athersys and its collaborating clinical investigators are highly motivated by the FDA’s authorization that we may proceed with enrollment of the first open-label cohort to evaluate safety ... We believe that MultiStem treatment, by modulating patients’ hyperinflammatory response to highly pathogenic respiratory viruses, including SARS-CoV-2 which causes COVID-19, represents a very promising approach to improving outcomes in patients who suffer the most severe manifestations of these illnesses.”
Two days after that announcement, the company also reported that the FDA had authorized an IND application to initiate a Phase 2 clinical trial evaluating MultiStem for early treatment of traumatic injuries and the subsequent complications that result following severe trauma.
A frequent complication following trauma is the occurrence of systemic inflammatory response syndrome (SIRS), which can contribute to organ failure or other severe complications. MultiStem has shown promise in reducing the hyperinflammatory response that occurs in a range of situations, by upregulating key reparative mechanisms that may reduce complications and meaningfully improve patient recovery.
“Based on results from previous clinical experience evaluating MultiStem in other critical care indications, such as ischemic stroke and acute respiratory distress syndrome—as well as published studies in models of traumatic brain injury, spinal cord injury and other forms of trauma—we believe that the early administration of MultiStem cells can meaningfully mitigate, or lessen, the overt and often detrimental inflammatory cascade that results from the activation of the immune system following occurrence of traumatic injury,” noted Dr. Robert W. Mays, vice president of regenerative medicine at Athersys, who added that he was particularly pleased with the quick response to the IND given the stresses on the FDA during the COVID-19 pandemic.
As previously disclosed, the trauma study is being supported under a grant awarded to McGovern Medical School at UTHealth from the Medical Technology Enterprise Consortium. The Memorial Hermann Foundation will provide additional funding. The study will be conducted under an Athersys IND, and Athersys will provide the investigational clinical product for the conduct of the trial, as well as regulatory and operational support. The trial protocol authorized by the FDA will be reviewed by the UTHealth Institutional Review Board to provide approval before trial initiation.
“We believe that the timely administration of our MultiStem cell therapy, regardless of the nature of the acute injury, could lead to fewer complications, quicker recoveries and a better long-term outcome for patients,” added Mays. “The authorization of this study by the FDA is an important step forward that will help us better understand the potential of our technology in this clinical indication.”