Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!
1. The first commercial “stem cell drug” approved in Japan
Two days ago, Australian company Mesoblast jointly with Japanese company JCR Pharmaceuticals announced “full approval” of Temcell – allogeneic mesenchymal stromal cell-based product – in pediatric acute GVHD. TemCell is a “former Prochymal”, developed by Osiris Therapeutics. Prochymal assests were acquired by Mesoblast in 2013 for $100M. To my knowledge, this is the first “stem cell drug”, approved in Japan under new “regenerative medicine law”. From JCR press release:
TEMCELL® HS Inj. is a product which JCR developed in Japan for the treatment of Acute GVHD, a severe complication arising from hematopoietic stem cell transplant utilizing the technology licensed-in from Osiris Therapeutics, Inc.* in 2003. As the first regenerative medicine product, TEMCELL® HS Inj. was granted full approval under a similar approach as that for a new drug.
JCR really really wanted it to happen. In 2003 they made a deal with Osiris for commercialization of Prochymal in Japan. In 2013, with acquisition of Prochymal by Mesoblast, JCR had to re-do the deal. It took 12 years for JCR to reach a goal. JCR conducted pivotal trial, independently of Osiris/ Mesoblast to prove that the product will work on Japanese patient population. Since JCR licensed Prochymal from Mesoblast, they have their own manufacturing site. Even though acute pediatric GVHD market is really small (I’d estimate few hundreds patients per year), both Osiris and Mesoblast will benefit financially from this approval and sales.
2. Complications of stem cell therapy – clinical cases
This week, I came across of 2 clinical cases, related to potential complication of stem cell therapy. Disseminated Mycobacterial infection was recently described in the patient, who traveled to Thailand for fetal stem cell therapy:
After the infusions, she felt generally ill with fever, malaise, and fatigue for the following 2 weeks before improving and returning to the United States. Within days of her return, she began to note purple-brown nodules on her legs with new lesions erupting every few weeks.
it is not the first case of Mycobacterial infection after cell therapy.
The second case is not related to medical tourism, but associated with authorized clinical trial. Gene-modified encapsulated mesenchymal stromal cells were transplanted in the brain of patients with hemorrhagic stroke. Three years later one patient developed cerebral arteriovenous malformation (in location of cells transplantation) with neurological symptoms. Even though, there was no prove for direct link of this pathological structure with cell therapy, the authors hypothesized:
De novo formation of a cerebral AVM has been observed only in 16 cases so far. The development of an AVM within 3 years after implantation of the GLP-1–secreting CellBeads suggests a possible relationship. Possible pathomechanisms include a local response to potentially angiogenetic peptides secreted by the MSCs or the GLP-1 itself, which may promote endothelial cell proliferation and angiogenesis. A foreign body reaction against the polypropylene mesh may also need to be considered.
The trial was terminated after treatment of 11 patients, due to decision to re-design cell encapsulation/ delivery platform.
3. UK is moving closer to CRISPR-based editing of human embryos
About 2 weeks ago, 5 UK agencies stated that they would not oppose a genome editing research on human embryos. This week, UK media reported that researcher Kathy Niakan asked government for permission to proceed with CRISPR-based editing of human embryo project:
Scientists working at The Francis Crick Institute (the Crick) in London have applied to the Human Fertilisation and Embryology Authority (HFEA) to use new “genome editing” techniques on human embryos.
Should the licence application be successful, the aim of the research, led by Dr Kathy Niakan, a group leader at the Crick, is to understand the genes human embryos need to develop successfully.
The work carried out at the Crick will be for research purposes and will not have a clinical application.
I don’t see any problem with approval of this proposition. I hope, UK will OK it soon.
4. Generation of vasculature in bioengineered decellularized organ
Harald Ott’s lab continues to improve whole organ bioengineering. This week, very important study from Ott’s group was published in Nature Biotechnology. Researchers were able to “endotheliaze” rat and human lungs with some success:
We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol. Using these methods we achieved ~75% endothelial coverage in the rat lung scaffold relative to that of native lung.
The results of human lungs endothelialization were not so impressive. About 5% of recellularized lung was covered by iPS cell-derived endothelium after few days in culture.
5. Optogenetic control of memory
Researchers from South Korea created new optogenetic platform, which allow to control of cellular calcium. OptoSTIM1 is plant-human hybrid protein. Previous attempts to control cellular calcium were not very accurate and efficient. After in vitro tests on ES cells and brain cells, the authors moved to experiments with memory control in mice:
Building on previous mice memory studies and their success with cultured hippocampal cells, they introduced OptoSTIM1 to the hippocampus of a living mouse. To test the functional effect of the Ca2+ influx, the IBS team compared sets of light-illuminated mice to non-illuminated mice expressing OptoSTIM1 in an environment where they introduced a conditioning cue followed by a fear stimulus. In subsequent tests they observed that light-illuminated mice with the OptoSTIM1 expression had a greater fear response when placed in the testing environment without the conditioning cue than the non-light-stimulated mice. In fact, they had a nearly twofold increase in fear stimulus response memory compared to non-light-stimulated mice, indicating that the OptoSTIM1 expression (and resultant Ca2+ uptake) was an effective method for memory enhancement.
Guys, you better remember name of this optogenetic tool – OptoSTIM1.
6. New advance in tissue clearing
Tissue clearing is a family of techniques, which allow to visualize spacial relationships between cell network by making tissue transparent. New addition to the family called ScaleS, was recently described by Japanese researchers from RIKEN Institute:
Previous methods were limited because the transparency process itself can damage the structures under study.
The original recipe reported by the Miyawaki team in 2011—termed Scale—was an aqueous solution based on urea that suffered from this same problem. The research team spent 5 years improving the effectiveness of the original recipe to overcome this critical challenge, and the result is ScaleS, a new technique with many practical applications.
The new technique creates transparent brain samples that can be stored in ScaleS solution for more than a year without damage. Internal structures maintain their original shape and brains are firm enough to permit the micron-thick slicing necessary for more detailed analyses.
7. Interview with George Church on the future of human genome editing
George Church is one of the prominent researchers in CRISPR-based genome editing from Harvard University. Here is one of his latest interviews, given to New Scientist. A quote about safety of genome editing in human:
So you’re not worried about the ethical issues that have been raised?
For me, the safety issues are the ethical issues, and the safety issues are not fundamentally different from those of any new therapeutic. Gene-editing techniques are being tested in animals extensively, in primates as well as rodents, and will eventually move into people.
8. Recent reviews:
Role of extracellular RNA-carrying vesicles in cell differentiation and reprogramming (Stem Cell Res Ther)
A comparison of non-integrating methods for patient-specific iPSC production (Stem Cell Rev Rep)