Cells Weekly – June 12, 2016

by Alexey Bersenev on June 13, 2016 · 0 comments

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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!

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1. Genomic analysis of multiple pluripotent stem cell lines sets quality standards
Scientists of NIH-funded “Progenitor Cell Biology Consortium” reported first results of genomic analysis of 64 human iPS/ES cell lines from 10 laboratories. Interestingly, only 64% of lines met “basic quality criteria”, some of them were contaminated. Raw data from this ongoing analysis are accessible via Synapse platform.

The resource presented here provides a standardized and annotated dataset for the characterization of hESC and iPSC that can be applied to the discovery of molecular determinants underlying specific biological properties of iPSC and their use for future clinical applications.

Senior author said:

“It was very surprising to us the high number of unstable cell lines identified in the study, which highlights the importance of setting safety standards for stem cell therapies,” said Carolyn Lutzko, PhD, senior author and director of translational development in the Translational Core Laboratories at Cincinnati Children’s Hospital Medical Center. “A good number of the cell lines we studied met quality standards, although the unexpected number of lines that did not meet these standards could not be used for clinical therapies.”

2. Clinical trials update
I’ve picked two clinical trials, results of which were published this week. First, Canadian Ph2 study, which assessed hematopoietic cell transplantation in multiple sclerosis. Some patient stories and mass media reporting made a big buzz about positive results of the trial. The study was small (n=24), uncontrolled, but results are really impressive. Cautionary note:

The lead author, Mark Freedman, of the University of Ottawa, was cautious about how the results should be interpreted, saying, “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results.
“Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centres experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial.”

The second study, assessment of commercial Tigenix product-candidate (Cx611) in refractory rheumatoid arthritis. Allogeneic adipose tissue-derived mesenchymal stromal cells were infused intravenously in 3 different doses (3 cohorts of patients). 141 adverse events were observed in 53 treated patients, but the authors deemed it as “non-toxic, well tolerated” intervention. Interestingly, there was no direct dose – clinical effect correlation observed. The lower dose was the most efficacious.

… a trend for clinical efficacy was observed. These data, in our opinion, justify further investigation of this innovative therapy in patients with RA.

3. Advance in antibody-based bone marrow conditioning
Researchers from Harvard described a new experimental method of condidtioning preparation for hematopoietic stem cell transplantation. Unlike conventional toxic radiation and chemotherapy, the authors used antibody for precise depletion of hematopoietic cells in bone marrow:

Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity.

The idea of using antibody-based conditioning is not new and it has reached the clinical trials. However, CD45 antibody in a form of immunotoxin, seem like more precise and less toxic approach.

4. New method for in vivo selection of gene-modified cells
Markus Grompe’s lab reported a methodology for efficient selection of gene-modified liver cells in vivo. How it was done:

Alongside the therapeutic transgene, the authors inserted into hepatocytes a short hairpin RNA targeting an enzyme that, when knocked down, made the cells resistant to a drug called CEHPOBA. Healthy animals received liver-specific vectors to express a model gene, human factor 9, and then were given CEHPOBA or saline for several weeks. The animals receiving saline control saw no change in gene expression in hepatocytes, whereas animals receiving the drug CEHPOBA saw an order of magnitude increase in factor 9, indicating that the gene-corrected cells were pharmacologically selected in a living animal.

Great model, but maybe very toxic. Comments on potential toxicity:

But what about the dangers of using a drug to deliberately injure liver cells? Grompe says that is not as risky as it sounds because babies are sometimes born with a condition that mimics the liver-damaging effects of the CEHPOBA drug. Yet they can fully recover if treated.

Kathy High, president of Spark Therapeutics, a gene therapy company in Philadelphia, Pennsylvania, calls the new strategy “clever,” but she’s wary of injuring any liver cells deliberately.

5. New methods and protocols:
Isolation and expansion of human MSC from placenta (JOVE)
In vivo tracking of human hematopoiesis using vector integration sites (Cell Stem Cell)
Influence of factors of cryopreservation and hypothermic storage on MSC (PLoS ONE)
Adaptation of a low-cost 3D-printer for precise cell placement (Biofabriacation)
Culturing human pluripotent and neural stem cells in an enclosed cell culture system (JoVE)
Quantitative lineage tracing to identify multiple lineages of tissue-specific stem cells (Gen Dev)

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