Cells Weekly – July 24, 2016

by Alexey Bersenev on July 25, 2016 · 0 comments

in notes

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. CRISPR clinical trial in China
Nature reported this week about the world’s first clinical trial, involved CRISPR gene edited cells. The trial is planning to start next month in China:

A team led by Lu You, an oncologist at Sichuan University’s West China Hospital in Chengdu, plans to start testing such cells in people with lung cancer next month. The clinical trial received ethical approval from the hospital’s review board on 6 July.

Lu’s team will extract immune cells called T cells from the blood of the enrolled patients, and then use CRISPR–Cas9 technology — which pairs a molecular guide able to identify specific genetic sequences on a chromosome with an enzyme that can snip the chromosome at that spot — to knock out a gene in the cells. The gene encodes a protein called PD-1 that normally acts as a check on the cell’s capacity to launch an immune response, to prevent it from attacking healthy cells.

Here is a link to the trial. A month ago, NIH RAC recommended similar trial in US, however its approval by FDA may take many months. China now is taking a lead in clinical use of CRISPR gene editing technology.

2. Results of stem cell therapy trial in ALS
Israeli company Brainstorm announced top line results of their Phase 2 clinical trial, assessing induced bone marrow mesenchymal stromal cells in patients with ALS. Importantly, this trial was designed as randomized, double-blinded and placebo-controlled. 48 patients were enrolled in 3 US centers. The study met primary end point – safety. The efficacy end points yielded mixed results at different time points. Based on functional score, used in ALS, cells-treated patients demonstrated clear benefit at 2 weeks post-therapy, which declined at later time points (8, 12 and 24 weeks):

At two weeks post treatment, 74% of NurOwn patients were responders, compared to 46% of placebo patients.
At eight weeks, the difference narrowed to where there was basically no difference in the response rates between NurOwn and placebo.
But at 12 weeks, 28% of NurOwn patients were still responders compared to just 8% of placebo patients. At 24 weeks, the end of the study, four NurOwn patients (11%) remained responders while all of the placebo patients had progressed. There were zero placebo responders.

3. Bioprinted tissue in predictive toxicology
Researchers from bioprinting company Organovo and BioPharma giant Roche, recently published a proof-of-principle study, demonstrating advantage of 3D printed patient-derived liver tissue over conventional methods in toxicology.

In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates.

They tested this system on Trovafloxacin (Trovan)- withdrawn drug with hepatotoxic potential. The toxicity of this drug was not identified in standard pre-clinical tests and it was approved in 1998.
Significance of this study nicely described in the Motley Fool:

Truvan was withdrawn from the market in Europe after multiple people died from liver failure after taking the drug. Since 1999, the antibiotic has only been available in the U.S. for emergency use. Rezulin’s story is similar. First approved by the FDA in 1997, Rezulin was taken off the market in 2000 after being linked to deaths resulting from liver failure.
In both cases, clinical studies failed to detect the potential for liver damage with the drugs. The end results were millions (and even billions) of dollars lost — and patient deaths.
Organovo hopes that studies like the one recently published will help drugmakers appreciate the value of 3D bioprinted tissues. Between 1990 and 2010, there were 39 drugs withdrawn from the market. Ten of those drugs caused liver damage, but the toxicity wasn’t picked up in testing. Another 13 drugs caused cardiovascular problems.

4. Stories from gene therapy trials
Antonio Regalado of MIT Tech Review and Ricki Lewis of DNA Science Blog this week posted some great patient stories from gene therapy trials. I’d highly recommend you to read them both:
Gene Therapy Trial Wrenches Families as One Child’s Death Saves Another (MIT Tech Review)
Hannah Has Her Gene Therapy for GAN: When Science Becomes Medicine (DNA Science Blog)

5. Adipose tissue serves as a niche for cancer stem cells
Research group, led by Craig Jordan recently demonstrated that adipose tissue serves as a niche for leukemic stem cells:

Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36+ LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment.

6. Debate on naive pluripotency state
Rudolf Jaenisch group from MIT publishes a lot on naive pluripotency. One of their latest studies, published in Cell Stem Cell was disputed by another prominent stem cell researcher Jacob Hanna on PubMed Commons and PubPeer. More about Hanna – Jaenisch clash read on the Niche blog.


Cells Weekly – July 17, 2016

by Alexey Bersenev on July 18, 2016 · 0 comments

in notes

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. Resolving Betatrophin controversy
I’ve followed controversy around pacreatic beta-cells growth factor betatrophin, described by Harvard’s Doug Melton (read here and here). This week, “controversy resolution” report was published in PLoS ONE (emphases mine):

To resolve the controversy, three independent labs collaborated on a blinded study to test the effects of ANGPTL8 upon β-cell proliferation.

The results demonstrate that ANGPTL8 does not stimulate significant β-cell proliferation. Each lab employed different methods for β-cell identification, resulting in variable quantification of β-cell proliferation and suggests a need for standardizing practices for β-cell quantification. We also observed a new action of ANGPTL8 in stimulating CD45+ hematopoietic-derived cell proliferation which may explain, in part, published discrepancies. Overall, the hypothesis that ANGPTL8 induces dramatic and specific β-cell proliferation can no longer be supported.

I applaud to this collaborative effort! I wonder now what will happen with original Melton’s 2013 paper in Cell?

2. The first bioprinting web cloud
Bioprinting startup BioBots, has announced the first bioprinting world cloud – Build With Life. About the project from their newsletter:

That’s what we call our wiki, it’s full of protocols, experimental reports and all sorts of useful biofabrication things…

As of now, the cloud built-in in company’s web-site and composed of 3 parts: Wiki, protocols and bioreports. I think, this is great initiative and unique for bioprinting community.

3. Big acquisitions in cell bioprocessing tools industry
I could not miss two very recent industry events – acquisitions of cell manufacturing tools companies. First, Sartorius Stedim acquired startup company kSep Systems for ~$28M. kSep is large-scale centrifuge-based system for washing and concentration of cell products and other biologics.
Second, GE Helthcare acquired Swiss company BioSafe Group. BioSafe is a manufacturer and supplier of well-known cell bioprocessing system Sepax. These deals show that besides therapeutic area, bioprocessing tools area is very hot in cell therapy industry as well.

4. Tumoriigenicity and immunogenicity of directly reprogrammed cells
The safety of cells, induced into different lineages via direct reprogramming, remains a big open question. In the recent study, published in Scientific Reports, researchers compared tumorigenicity and immunogenicity of induced neural cells (iNSC) with iPS or ES cells or with adult neural stem cells and MSC in the model of syngenic transplantation into mouse brain:

We demonstrate that iPSCs, as well as ESCs, can form tumours in mouse brains, leading to tissue destruction and immune cell infiltration. In contrast, we report no evidence of tumour formation, brain injury or immune rejection in the iNSC, NSC, and MSC groups. Therefore, iNSC grafts are safer than iPSC grafts, with no resulting tumourigenicity or immunogenicity.

5. Commercial potential of gene therapy
Biotech analyst Ohad Hammer, have recently written interesting post on Open Reading Frame blog about gene therapy. He overviews potential catalysts and recent developments in gene therapy companies. He asks whether gene therapy could be a new growth driver Biotech industry in 2017 and sparks discussion in comment section.

While there are several hot areas in biotech such as gene editing and microbiome, most are still early and their applicability is unclear. Gene therapy, on the other hand, is more mature and de-risked with tens of clinical studies and the potential to treat (and perhaps cure) a wide range of diseases where treatment is inadequate or non-existent. The commercial upside from these programs is huge and should expand as additional indications are pursued.

6. Fresh reviews:
Platelet lysate as a substitute for animal serum for the ex-vivo expansion of MSC (Stem Cell Res Ther)
Current progress and future prospects in brain organoid research (Dev Biol)
The tumorigenic potential of pluripotent stem cells: What can we do to minimize it? (Bioessays)
Aging of hematopoietic stem cells: DNA damage and mutations? (Exp Hematol)

7. New methods and protocols:
Isolating mesangiogenic progenitor cells from human bone marrow (JoVE)
Serum-derived protein removes the need for coating in defined human pluripotent stem cell culture (Nat Commun)
ZNF-based gene editing of iPSCs from a Wiskott-Aldrich syndrome patient (Stem Cel Rep)
Purification protocol for retinal pigment epithelium from mouse iPS cells as a research tool (PLoS ONE)
Cryopreservation of bone marrow mononuclear cells alters their viability and composition but not their therapeutic effects in stroke model (Stem Cells Int)


I’ve written before about Pieman Hematti’s opinion piece on Similar identity of mesenchymal stromal cells (MSC) and fibroblasts. Recently, Hematti’s lab published results of new study, which attempted to find any phenotypic and immunological differences between fibroblasts and MSCs.

Four well-established, widely used fibroblasts cell lines from 3 different original tissues were compared with adipose tissue- and bone marrow-derived MSCs. The authors used the following series of methods to compare these 2 cell types:

  • Cell morphology in culture (microscopy)
  • Immunophenotyping by frow cytometry (basic ISCT criteria and more markers)
  • Three-lineage differentiation (adipo- chondro- osteo-)
  • Immunological: response to IFN-gamma stimulation, suppression of T-cell proliferation, macrophages activation
  • Extracellular matrix protein production (fibronectin and collagen)

The conclusion – based on all these methods, fibroblasts and MSC were absolutely indistinguishable! The authors are discussing controversies in the literature, related to discrimination of fibroblalsts and MSC, but they are coming to conclusion that all differences, described by other groups as minor as differences between MSC from different tissue sources and were found mostly in gene expression:

… it is also well known that even fibroblasts display distinct and characteristic transcriptional gene expression patterns depending on the anatomic site or origin [55,56]. Furthermore, the magnitude of the differences reported in the literature between MSCs and fibroblasts is comparable to differences reported in the literature among MSCs derived from different tissues. In studies where fibroblasts and MSCs have been reported to be different, these differences are no greater than the differences between MSCs from different tissues or between fibroblasts from different tissues [18]. Given that differences in culture conditions or derivation methodologies could affect the phenotype of these cells [57,58], it is not surprising that such differences are found in gene expression studies that compare MSCs and fibroblasts.

So, Hematti has been proposing for years that MSCs and fibroblasts “could likely represent the same cell type”. I’ve not seen any response and commentaries of “MSC guys” to Hematti’s proposal. Interestingly, the recent study, published in Stem Cells TM describes the difference between dermal fibroblasts and adipose tissue-derived MSC in their secretome. Measure of VEGF and SDF-1 is proposed as rapid method for discrimination of these 2 cell types, based on metabolism/ secretome.

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Cells Weekly – July 10, 2016

by Alexey Bersenev on July 10, 2016 · 0 comments

in notes

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 end of Chondrocelect
Beligian cell therapy company Tigenix announced plans for withdrawal of their autologous chondrocytes implantation product Chondrocelect from European market. This is business decision, due to competitors on a market and lack of reimbursement. Chondrocelect received EMA marketing authorization in 2009. From company’s press release:

Due to the regulatory environment around autologous chondrocyte-based cell therapy products in Europe leading to a difficult competitive landscape for ChondroCelect, together with the lack of reimbursement in key European countries, TiGenix has been prompted to initiate the withdrawal process of the Marketing Authorization for ChondroCelect® for commercial reasons. Consequently, TiGenix has come to an agreement with Sobi for the early termination of their existing commercial relationship and will also terminate its manufacturing agreement with PharmaCell.

I think, this is big blow for the field. One more cell therapy product was not doing well on a market after approval. Now it’s a part of history. For quite similar reasons, Genzyme/Sanofi withdrew their ACI product MACI in different countries and closed manufacturing sites.

2. FDA under pressure
As one of repercussions of “US stem cell clinics study”, published last week, Nature’s editorial blamed FDA in weak regulation:

The claim that regulation is too harsh wrongly implies that the FDA is holding back therapies that work. Critics point to decades of preclinical and clinical work with stem cells and the pipelines of stem-cell treatments. With circular logic, they argue that, because the treatments have not been approved, there is something wrong with the approval system.
The assumption in these accusations — that these treatments work — is at the heart of the problem. The FDA is right to insist that only proper clinical trials can make that case. And the agency’s critics are right to point out that this process is lengthy and expensive — perhaps too much so.

I think, the editorial got some things right (for example, yes – absence of stem cell products on a market does not necessarily mean that FDA is too harsh, it could means that all product-cadidates are suck), but some statements could be wrong or too simplified. Nature is bringing Turner/ Knoepfler study to say “that the FDA is not unduly harsh”. But it could be not the case. It could be because FDA does not have enough funding and manpower to fight with a scale of these clinics and police all of them. We do not know for sure. Another thing is that editorial portrays new Japanese Regenerative Medicine law as “patients rip-off”, but not like conscious decision of government and people of Japan.

3. Deaths in CAR T-cell therapy trial
CAR-T Deaths Cannot Be Good (In The Pipeline) – read comments!
CAR T-cell therapy developer Juno Therapeutics announced clinical hold of their Phase 2 ROCKET trial, triggered by death of patients. The trial was suspended by FDA. Because CAR T-cells is currently the hottest area of cell therapy, Juno’s news made a big buzz in the social media. Links to some interesting coverage below:
Juno Therapeutics Stops Trial Of Cancer-Killing Cells After 3 Patient Deaths (Forbes)
Juno scrambles to avoid being crushed by a hold, but experts question its best case scenario (EndPoints)
Are patient deaths in the Juno cancer trial just a ‘bump in the road’? (STAT/ Pharmalot)
Is Juno’s hold a CAR crash or just a speed bump? (EP Vantage)
Unexpected Deaths Put Promising Immunotherapy on Hold (MIT Tech Review)

4. CAAR-T cells for targeting of autoimmune diseases
Researchers from University of Pennsylvania for the first time described new type of CAR T-cells, engineered to target auto-antigen – chimeric auto-antibody receptor T-cells (CAAR). From NIHilist’s Immunology blog:

This new technology is based on a simple idea: antigen decoy. For example, during pemphigus vulgaris autoimmune B cells secrete autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg3) that causes severe skin inflammation. Short-term management of diseases is achieved by total B cell depletion, but disease returns. The authors reasoned that if engineered T cells would express Dsg3 as a CARs, such antigen decoy CAAR T cells would selectively engage disease-causing anti-Dsg3-specific auto-antibody producing B cells. Such interaction should eliminate only Dsg3 specific B cells, sparing normal, infectious-specific B cells.

5. Stem cell gene therapy in Gartner Hype-Hope curve
LifeSci VC blog posted very interesting analysis of hype-hope cycle in so-called stem cell gene therapy (means CD34+ cell-based gene therapy of inherited immunodeficiencies). This analysis is based on recent EMA approval for gene therapy product Strimvelis (GSK). The authors think that European approval of Strimvelis is a first sign of “plateau of productivity” in Gartner’s curve:

With a switch from T cells to stem cells and a roller-coaster hype ride, the gene therapy field has delivered on its promise from over 25 years ago with a medicine that now offers a real hope for children with ADA-SCID. At the heart of the journey to Strimvelis are patients and their families, starting with Ashanti DeSilva who was the first ADA-SCID patient to receive gene therapy with her own modified T cells. We owe a huge debt to the brave families who enrolled their children on clinical trials, together with the clinical giants who led this work and provided vital learnings for the adjacent fields for the future. The next chapters for CAR-T and gene editing will be compelling, especially if they are able to both seed new technology developments and bring curative medicines to patients.

6. Shoukhrat Mitalipov’s profile
STAT posted a profile article about mitochondrial genome transfer pioneer Shoukhrat Mitalipov. Very good article, highly recommended!

His whole career, Mitalipov said, has consisted of tinkering with the nuclear transfer techniques that Campbell, who died a few years ago, developed in the mid-90s.
“My clinical goal was to use some of the basic knowledge to improve human reproduction,” Mitalipov said. “The IVF platform can be used now to remanufacture gametes, to treat infertility, but also as a platform for gene therapy, which is probably where the future will go.”

7. Trends in NIH-funded stem cell workforce
The authors of recent analysis, published in Cell Stem Cell, looked at aging of NIH-funded workforce with focus on stem cell research. Take home message – more government money go to older stem cell researchers. More detailed conclusions:

The stem cell research workforce has expanded over the past decade and a half. Even though it is a “relatively” new field given NIH’s history, it faces some of the similar issues experienced by the entire research community. It is also aging. The number of NIH R01-equivalent applications from older stem cell investigators has been growing at a faster rate than younger investigators and competition for funding is intense. However, retirement-age replacement ratios are increasing. As with the entire biomedical research workforce, stem cell researchers who are dependent on NIH for research funding will also have to examine the culture and environment in their institutions and work with federal agencies and other funders to find creative and innovative solutions to help reduce the stress on an aging workforce system within a limited-resources environment.

Also read coverage by Science 2.0

8. Fresh free reviews:
Human-animal chimeras: ethical issues about farming chimeric animals bearing human organs (Stem Cell Res Ther)
Cellular Reprogramming Using Defined Factors and MicroRNAs (Stem Cells Int)
Efficacy of MSC therapy for acute lung injury in preclinical models (PLoS ONE)


Cells Weekly – July 3, 2016

by Alexey Bersenev July 4, 2016 notes

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. Proliferation of “unproved stem cell clinics” in US The biggest buzz this week was a study by @LeighGTurner and @pknoepfler on “stem cell clinics” in US. […]

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Clinical Cell Processing News – part 3, 2016

by Alexey Bersenev July 2, 2016 clinical lab

Clinical Cell Processing News is a series about new protocols, products and techniques for clinical-grade cell processing and manufacturing. Cell processing devices, cultureware, bioreactors, GMP-grade reagents, cell separation techniques. This series is posted every 2 months. FEATURED: Protocol: PBMC isolation protocol using SynGenX-LAB System (SynGen) Validation of CliniMACS Prodigy for clinical CAR T-cell manufacturing (Cytotherapy) […]

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Cells Weekly – June 26, 2016

by Alexey Bersenev June 27, 2016 notes

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. Coverage of ISCCR 2016 Annual meeting of International Society for Stem Cell Research (ISSCR) is a main scientific event in the stem cell field. I was […]

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Some thoughts on US Cell Manufacturing Roadmap

by Alexey Bersenev June 23, 2016 notes

As you may know, last week US-based National Cell Manufacturing Consortium issued very interesting report – Cell Manufacturing Roadmap. What is it all about? Here is a quote from the report, which gives background information: The Georgia Research Alliance (GRA) and Georgia Institute of Technology (Georgia Tech) recognized the opportunity to advance innovative technologies and […]

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Cells Weekly – June 19, 2016

by Alexey Bersenev June 20, 2016 notes

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. Cell manufacturing roadmap US-based National Cell Manufacturing Consortium issued this week the first document – Cell Manufacturing Roadmap. The roadmap is a collaborative project, which outlines […]

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Cells Weekly – June 12, 2016

by Alexey Bersenev June 13, 2016 notes

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. 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 […]

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