• Cryopreservation of mesenchymal stromal cells can attenuate clinical immune effects
    As Jacques Galipeau reported in conferences and in the paper, cryopreservation could negatively affect therapeutic “immunomodulatory value” of mesenchymal stromal cells (MSC). There was no independent confirmation of Galipeau’s findings, and many MSC product developers remained skeptical. This week, Katarina Le Blanc published a report, which supports Galipeau’s conclusions and provides more insight into potential clinical value of this phenomenon. Let me just say – this paper could change the field! Le Blanc concluded that freeze-thawed human MSC compared to […]
  • 10 companies to watch – part 4

    by Alexey Bersenev on March 30, 2015 · 0 comments

    in RegenMed digest

    Welcome to the 4th issue of Ten Companies to Watch – one of the most popular series on our blog! Here I pick and overview the most interesting new companies in stem cell/ cell therapy/ regenerative medicine field. I’m focusing on startups, but considering any other “under-appreciated” companies. As always – I’m open to your suggestions. Tell me why any particular company is different and worth our attention.

    Ok, here is new list without particular order:

    1. Unum Therapeutics
    Cellular immunotherapeutic, clinical stage startup from Cambridge (MA), founded last year. The company develops cell therapeutic platform, based on so-called Antibody-Coupled T-cell Receptor (ACTR) technology. Competitive advantage of ACTR, compare to CART cell therapy, is possibility of creating “universal T-cells” for multiple targets. The action of ACTR is antibody-directed. The company has started clinical trial for hematological malignancies last year in Singapore.

    2. Videregen
    UK-based startup, founded in 2011. The company is commercializing recell-decell approach to whole organ engineering for transplantation. Starting from hollow organs (trachea and small bowel), Videregen is planning to move to such complex solid organs as liver.

    3. Sulfateq BV
    Dutch startup, founded in 2011. The company attracted my attention via LinkedIn promotion of their innovative product Rokepie. This cell culture media supplement allows short-term cell biopreservation via hibernation. Rokepie is synthetic non-toxic product, which can keep your cells well in the cold for 1-3 weeks. So far – research use only, but clinical applications on a horizon. Learn more from this video.

    4. SQZ Biotech
    Startup company from Cambridge (MA), spin out of MIT, founded in 2013. The company makes microfluidic device (chip), which allows intracellular delivery of genetic material via mechanical squeezing of cells. It could potentially disrupt all known gene delivery platforms. It’s easy, fast and cheap. Read more here.

    5. BioBots
    Bioprinting startup company from Philadelphia (PA), founded in 2014. Competitive advantage of Biobots, compare to other bioprinting companies is low-cost easy to use desktop bioprinter. The company is making an impact by democratizing bioprinting research via collaboration with multiple labs.

    6. MirImmune
    Newly formed startup from Cambridge (MA). The company is trying to combine and commercialize two very hot technologies – adoptive T-cell therapy and silencing of immune checkpoints by RNAi. The recent deal with RXi Pharmaceuticals captures my attention to the company.

    7. Universal Cells
    Pre-clinical stage, startup company from Seattle (WA), founded in 2013. The company can modify allogeneic therapeutic cells, making them “un-rejectable”. HLA expression altered by AVV-mediated genome editing.

    8. Semma Therapeutics
    Newly formed startup from Cambridge (MA). Spin out of Harvard U, which utilizes technology for manufacturing beta-cell therapeutic product for diabetes, developed in Doug Melton’s lab. This is the latest buzz from hot Cambridge hub. Read more here.

    9. Spark Therapeutics
    Gene therapy clinical stage company, spin out of Children’s Hospital of Philadelphia, founded in 2013. With good clinical results in treatment of genetic eye diseases (inherited retinal dystrophies) and Breakthrough Therapy Designation by FDA, the company rapidly progressed to Phase 3 pivotal trial. Their product is a good candidate to become the first approved gene therapy drug in US. This year company started from successful IPO.

    10. Cell Habitats
    US-based, pre-clinical stage, regenerative medicine company, founded in 2005. The company is utilizing regenerative cell therapy in situ approach by providing artificial niches for endogenous stem cells. Company’s biomaterial-based micro-sized compound Regenerods able to attract and stimulate growth of tissue resident stem cells.

    *******************
    Disclaimer: This list reflects solely my opinion and sympathy. I have no financial interest in companies, mentioned in this post. This post should not be considered as financial advice.

    { 0 comments }

    Cells Weekly – March 29, 2015

    by Alexey Bersenev on March 29, 2015 · 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!

    CD34+Banner_490x90

    1. Using CAR T-cells in solid cancer – results of clinical trial
    CAR T-cell therapy in oncology is the a very hot topic right now. So far, it has been very successful in treatment of hematological malignancies. However, with exception of few cases, the results of using CAR T-cell therapy in solid cancers have not been published. This week, the first such report came up from MD Anderson Cancer Center. Researchers created HER2-specific CAR T-cells for treatment of sarcomas. Unfortunately, the results of solid cancer CAR trial are not as impressive as in leukemias:

    Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).

    2. Manipulation of master regulatory factor specificity leads to lineage conversion
    Very interesting study was recently published in Cell Reports – specific manipulation of myogenesis master regulator MyoD led to neurogenic lineage conversion. The authors achieved this by introduction to MyoD binding sites, specific for neurogenic master regulator – NeuroD2.

    … redirecting MyoD binding from MyoD private sites to NeuroD2 private sites, despite preserved binding to the MyoD/NeuroD2 shared sites, is sufficient to change MyoD from a master regulator of myogenesis to a master regulator of neurogenesis.

    3. Commercialization of “stem cell secretome”
    US-based stem cell therapeutic company Stemedica announced this week worldwide manufacturing license of their VitriLife product to subsidiary StemProtein. VitriLife is a “stem cell conditioned media”, stabilized by Preservation by Vaporization (PBV) technology. The product is vaporized and could be stored at ambient temperature for 2 or more years. I was kind of shocked by this (emphases mine):

    Stemedica products currently in development include eye drops, inhalable dry powders, wound dressings, injectable (parenteral) solutions, nose drops, sublingual tablets and a variety of skincare and dental products.

    and

    PBV preserves a mixture of macromolecules that are secreted by stem cells in culture. The thermostable mixture contains sensitive biologicals, such as cytokines, chemokines, growth factors, matricellular proteins, enzymes, mRNAs and microRNAs.

    If it contains biologicals, shouldn’t it be regulated appropriately?

    4. Adverse effects of adipose SVF spine injections in experimental model
    A group of authors from Netherlands recently described very interesting findings – severe adverse effects of adipose tissue-derived stromal vascular fraction (SVF) in goat intervertebral discs regeneration model:

    Unexpectedly, we observed a severe inflammatory response that has not been described before, including massive lymphocyte infiltration, neovascularisation and endplate destruction.
    Despite our quest for the responsible agent, we eventually could not identify the mechanism through which the observed destructive responses occurred. Although we cannot exclude that the adverse effects are species-dependent or model-specific, we advertise caution with the clinical application of autologous SVF injections into the IVD until the responsible agent(s) are identified.

    The procedure is gaining popularity among “private spinal clinics”, however results of this study, as well as 2012 clinical case, should alarm surgeons.
    via @CCentenoMD

    5. What is in cancer stem cell name?
    Sara Nolte wrote very interesting post for the Signals blog, which discusses the term “cancer stem cell” and targeting of self-renewing cancer cells:

    I ask again: what really is in a name? Cancer stem cell, cancer initiating cell, tumour initiating cell – while all referring to something specific scientifically, strip away the nuances, and you’re left with a cancer cell with stem cell properties. As our understanding of CSCs increases, we begin to see that we were more right than we knew in calling them cancer stem cells, as they are continually being shown to likely be misappropriated stem cells.

    6. Trends in embryonic stem cell research activity over 10 years
    Recent study, published in PLoS ONE, analyses trends in embryonic stem cell research between 2001-2010.

    This paper analyzes how the 2001 U.S. federal funding restrictions influenced the quantity and geography of peer-reviewed journal publications on hESC. The primary finding is that the 2001 policy did not have a significant aggregate effect on hESC research in the U.S. After a brief lag in early 2000s, U.S. hESC research maintained pace with other areas of stem cell and genetic research.

    8. SwissMedic crackdown on illegal cell therapies
    Interesting news from Switzerland:

    Swiss authorities say they have opened a criminal case against several unidentified health clinics and providers as part of a broader crackdown on hospitals and private clinics that illegally treat patients using unauthorised fresh cell therapy.

    9. New methods and protocols:
    Generation of human pluripotent stem cell derived lung organoids (eLife)
    Nuclear reprogramming with a non-integrating human measles virus (Stem Cells Res Ther)
    Role of Wnt3a protein in expansion of cord blood hematopoietic cells (PLoS ONE)
    Generation of expandable SOX9+ chondrogenic cells from human pluripotent stem cells (Stem Cells Reports)

    { 0 comments }

    Cell Gadgets Review – 2015 part I

    by Alexey Bersenev on March 24, 2015 · 0 comments

    in gadgets

    Cell Gadgets series is an overview of “smart devices”, biochips, matrices and biomaterials for research and therapy.

    1. Light-activated implantable smart hydrogel
    Researchers from Georgia Tech made a light-triggered hydrogel with cell adhesive peptide and growth factors. They demonstrated that transdermal UV light exposure can activate cell adhesion, inflammation and vascularization of hydrogel in vivo. The study published in Nature Materials.

    2. Microfluidic chip to deliver genetic material into the cell
    Mechanical squeezing of cells in microfluidics chip narrow channels makes cell membrane permeable to genetic material or drugs. This approach used by new startup company SQZ Biotech. If this technology will work as efficient as viral transduction, it may disrupt cell gene therapy market:

    In the longer run, Sharei said, CellSqueeze could be used in a therapeutic setting — say, by squeezing cancer-related proteins into human cells to teach people’s immune systems what to attack. Tests are not being done on humans yet. But if medical tests were to show success, CellSqueeze therapies could be done much more cheaply than other new anticancer treatments that involve changing the genes of individual cells, like CAR T cell therapy, Sharei said.

    3. BioGenerator for cardiac cell therapy
    NuVascular Technologies in collaboration with Worcester Polytechnic Institute, and BioSurfaces, Inc. has developed an implantable “stem cell device” for heart repair:

    The BioGenerator is a medical device consisting of two essential parts: a capsule made from BioSurfaces’ patented electrospinning technology, and stem cells derived from adult bone marrow at WPI. The BioGenerator can be stitched into the heart muscle wall or injected into the heart muscle itself through a catheter (Figure attached). Both options are minimally invasive, do not require open-heart surgery and allow the heart to repair itself. The encased stem cells release proteins and growth factors that move through the device into the heart muscle, stimulating the cardiac myocytes to grow and repair damage.

    4. Artificial bone marrow niche for platelets generation
    Italian researchers created artificial bone marrow niche from programmable 3D silk. The demonstrated platelets production from hematopoietic progenitor cells in vitro:

    A critical feature of the system is the use of natural silk protein biomaterial allowing us to leverage its biocompatibility, non-thrombogenic features, programmable mechanical properties, and surface binding of cytokines, extracellular matrix components and endothelial-derived proteins. This in turn offers new opportunities for the study of blood component production ex vivo and provides a superior tissue system for the study of pathologic mechanisms of human platelet production.

    5. Dielectrophoresis-based chip separates stem cells and their progeny
    New microfluidic continuous-flow chip, which based on dielectrophoresis, was tested on separation of mesenchymal stromal cells from their osteogenic progeny:
    Collection efficiency up to 92% and 67% for hMSCs and osteoblasts, respectively, along with purity up to 84% and 87% was obtained. The experimental results established the feasibility of our microfluidic DEP sorting device for continuous, label-free sorting of stem cells and their differentiation progenies.

    6. Holographic optical tweezers for cellular micromanipulation
    Scientists from University of Nottingham described a very precise tool – holographic optical tweezers (HOT) for micromanipulation of cells and their environment. They successfully created artificial niches from embryonic stem cells and biomaterials:

    We demonstrate the combination of a HOTs system with controllable and tailored structural elements including polymeric materials, ECM, controlled release microparticles and hydrogels. These elements were micro-manipulated into complex architectures precisely controlling physical and chemical factors to produce micro-environmental analogues.

    7. Printing nerve guidance conduits for neural repair
    Researchers from University of Sheffield used 3D printing for generation of nerve guidance conduits. Implantation of printed nerve conduits were able re-innervate 3 mm injury gap in 21 days and were comparable to autograft control. The study published in Biomaterials.

    The study provides a technology platform for the rapid microfabrication of biocompatible materials, a novel method for in vivo evaluation, and a benchmark for future development in more advanced NGC designs, biodegradable and larger device sizes, and longer-term implantation studies.

    { 0 comments }

    Cells Weekly – March 22, 2015

    by Alexey Bersenev on March 23, 2015 · 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!

    CD34+Banner_490x90

    1. Debate on gene modification of human germ line continues
    This week, more scientists speak out about pros and cons of human germ line gene modification. Scientists are divided on this topic. A “new bomb”, which heated discussions, was the paper published this week in Science. It was the most impressive phenomenon of gene drive and it was made by CRISPR-based genomic engineering of germ line:

    George Church, a geneticist at Harvard Medical School in Boston who is a leader in the field, believes the new study should not have been published, because it does not include measures to restrain the spread of unintended mutations. “It is a step too far,” he says

    ISSCR posted society’s official position (links is currently broken, try later) this week:

    The International Society for Stem Cell Research calls for a moratorium on attempts at clinical application of nuclear genome editing of the human germ line to enable more extensive scientific analysis of the potential risks of genome editing and broader public discussion of the societal and ethical implications.

    MIT Tech Review covered Science editorial and cited David Baltimore:

    “Scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical applications in humans,” they write.

    “You would be making changes in generations to come, in ways that are very hard to predict,” says Baltimore.

    Shamefully, Science magazine paywalled “CRISPR Revolution“.
    Yet another interesting piece from this debate – Paul Knoepfler’s practical plan for managing human germline modifications.

    2. Clinical trials update
    I’ve picked 3 trials results from this week. First, Russian study, which assessed mismatched cord blood transplantation in children with cerebral palsy. Patients received multiple infusions, no control groups:

    The results confirm that multiple intravenous infusions of allogeneic AB0/Rh-identical UCB cells may be a safe and effective procedure and could be included in treatment and rehabilitation programs for juvenile patients with cerebral palsy.

    The second study – results of Phase 1 trial for cord blood enhancement by fucosylation. Only 30 min of incubation with fucosylation enzyme allows to boost engraftment.

    These findings support ex vivo fucosylation of multipotent CD34+ CB cells as a clinically feasible means to improve engraftment efficiency in the double CBT setting.

    Cord blood fucosylation is commercialized by Targazyme. What is interesting here is a competition – very similar approach (but using PGE2) for cord blood enhancement is developed by Fate Therapeutics. Results of ongoing Fate’s trials are quite similar to Targazyme.
    Finally, results of the first clinical study, assessing “stem cell conditioned media” were published. Conditioned media from adipose-derived stem cell culture was used for treating of female alopecia:

    The application of ADSC-CM showed efficacy in treating FPHL after 12 weeks of therapy. Hair density increased from 105.4 to 122.7 hairs/cm2 (P < 0.001). Hair thickness increased from 57.5 μm to 64.0 μm (P < 0.001). None of the patients reported severe adverse reactions.

    Well, seem like sometimes we don’t even need cells!

    3. Lawsuit for post-publication peer review platform – PubPeer
    We love PubPeer and cite it all the time. This is a very valuable platform for scientific community. However last year PubPeer got into lawsuit – you can read about it here. 2 weeks ago court ruled in favor of PubPeer. However, this week the case took another turn:

    A Michigan judge has ruled against a motion by PubPeer to protect the identity of an anonymous commenter, and asked the post-publication peer review site to give her any information they have about the commenter.

    From ScienceInsider:

    One of PubPeer’s (anonymous) moderators told ScienceInsider: “If this decision creates a precedent, future online comment will be limited to trivial matters, while all discussion of serious matters will be discouraged by fear of legal entanglement.”

    Results of this case could be historic for scientific peer review process, science communication and self-correction.

    4. Interview with Edward Lanphier – chairman of the Alliance for Regenerative Medicine
    The Life Science Report posted very interesting interview with current chairman of ARM – an international regenerative medicine lobby organization. He shared ARM’s position and excitment about the future of the industry:

    If you could administer a one-time therapy to a very young child that causes him to express the normal human factor VIII protein at curative levels, the ultimate cost savings to the government and to payers could be enormous. If you then spread those savings across all of the disease areas where gene therapy and genetically modified cell therapies can be utilized, the cost savings are even more immense.

    5. Method for cell labeling and tracking after transplantation
    New method for cell tracking was described in PLoS ONE. Researchers used Fluorine-19 to label mesenchymal stromal cells. This marker could be tracked by MRI:

    Our results show that 19F-MRI is an excellent tool for verifying the delivery of therapeutic cells early after transplantation. However, in certain circumstances the transfer of cellular label to other bystander cells may confuse interpretation of the long-term fate of the transplanted cells.

    6. Evolution of xeno-free systems for human ES cell culture – review
    Very good review (freely available) was published this week – Human embryonic stem cell cultivation: historical perspective and evolution of xeno-free culture systems.

    Xeno-free culture models using extracellular matrices, biosynthetic surfaces and chemically defined media to create therapeutic grade hESC represent an important stepping stone in expanding such therapies. More data is still needed on the continued functionality of hESC cells after long term culture and continued passage in these new culture models.

    Highly recommended!

    7. New methods and protocols:
    Characterization of menstrual stem cells and their comparison with bone marrow MSCs (Stem Cell Res Ther)
    Xeno- transplant leukemia model using bioluminescence imaging (PLoS ONE)
    Large-scale expansion of Wharton’s jelly-derived MSCs on gelatin microbeads (Stem Cell Res Ther)
    Differentiation of human iPS cells to Purkinje neurons (Sci Reports)
    Reprogramming HUVEC into iPS cells and generation of neural cells (PLoS ONE)

    { 0 comments }

    Off-the-shelf universal molecular beacon

    by Alexey Bersenev March 18, 2015 cell separation

    Molecular beacon (MB) is a new tool to isolate cells, based on intracellular genetic marker. Specific molecular beacons were designed for positive selection of particular cell types. The next step in development of MB – universal RNA beacon – was recently described: Here, we report on an off-the-shelf universal beacon that targets a nonsense tag placed in the untranslated region of a functional protein or even a biomarker. We show that UB technology allows for detection and high-throughput separation of […]

    0 comments Read the full article →

    Cells Weekly – March 15, 2015

    by Alexey Bersenev March 15, 2015 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. Debate on genomic editing of germ line The discussion of the week – genome modification of human germ line. It was triggered by a letter, posted by Nature magazine, where a group of experts called for moratorium of human germ line gene modification practices: In our view, genome editing in human […]

    0 comments Read the full article →

    Products in the pipeline – Ocata’s RPE

    by Alexey Bersenev March 12, 2015 cell product

    This is 4th post of the series Products in the Pipeline. In this series we (community!) will provide publicly available information about therapeutic products – candidates for commercialization by cell therapy industry companies. ________________________________________ Prepared by m.cea for StemCellAssays.com, narrowed by Alexey Bersenev . Product candidate name: hESC-MA09 RPE (no trade name yet) Developer: Ocata Therapeutics Inc. (formerly Advanced Cell Technology Inc.) History of development: Since 2003 Type of cells: Human allogeneic embryonic stem cell-derived retinal pigment epithelium (RPE), expanded […]

    1 comment Read the full article →

    Cells Weekly – March 8, 2015

    by Alexey Bersenev March 8, 2015 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! Site update: Our crowdsourcing project – Clinical-grade media and supplements for mesenchymal stromal cell (MSC) manufacturing – is getting new comments from time to time. Please feel free to add information if something new came up on a market! 1. Cell therapy breakthrough designations by FDA This week, 4th cell therapy got […]

    0 comments Read the full article →

    Use of media and serum in clinical culture of mesenchymal stromal cells

    by Alexey Bersenev March 4, 2015 cell culture

    Last year I was trying to capture and analyze results of all published clinical studies in cell-based regenerative medicine. One dimension that I was able to capture is using of media and serum for mesenchymal stromal cell (MSC) clinical culture. Today, I’d like to share some data. You can read about the methodology of this analysis here. Out of total 116 regenerative medicine clinical studies, 45 used MSC culture. I was able to capture information about media/serum use from 36 […]

    0 comments Read the full article →

    Cells Weekly – March 1, 2015

    by Alexey Bersenev March 1, 2015 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. UK says YES to mitochondrial transfer techniques After long-term debate, UK’s House of Lords voted for approval regulation of mithochondrial transfer techniques to be used in clinic. This is a historic moment, because UK has become the only country, which took a risk to approve these highly controversial techniques. It could […]

    0 comments Read the full article →