Cells Weekly – January 18, 2016

by Alexey Bersenev on January 18, 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!

Cell & Gene Therapy World 2016

1. CRISPR patents war is heating up
This week there were a lot of news and emotional discussions on social media about interference between Doudna’s (U of Berkley) and Zhang’s (MIT) CRISPR-related patents. Interference was officially declared by US Patent Office. So, the battle “all-or-nothing” is coming:

Yesterday’s declaration of an interference proceeding already provides a few hints. First, it lists Doudna as the “senior party” and Zhang as the “junior party”—an initial determination that the administrative patent judge agrees that Doudna was the first inventor. This means that the burden of proof rests on Zhang, much like how, in a criminal trial, the government—not a criminal defendant—must prove its case beyond a reasonable doubt. Second, the declaration puts at issue all of the patent claims; none are left out. This suggests that the interference proceeding—assuming it retains its current scope—will be an all-or-nothing affair: Zhang will either get to keep all of his patents or lose all of them. This may mean that there is little room, legally, for the patent office to keep both sides happy.

Timely review by Broad Institute’s director, Eric Lander – The Heroes of CRISPR – was a bomb with many many splashes on social media. Read some discussions here, here, here, here, here and here.

I’ve picked some interesting posts and reporting on CRISPR patents interference case:
Bitter fight over CRISPR patent heats up (Nature)
The #CRISPR Interference: Doudna v Zhang. My thoughts. $EDIT (@psuvafan007)
A poll: Did Lander Cell piece on #CRISPR give Doudna due credit? (@pknoepfler)
CRISPR Patent War: Billions at Stake for UC Berkeley (KQED Science)

2. FDA cracks down on stem cell clinics
FDA issued a warning letter to Irvine Stem Cell Treatment Center, where outlined the serious issues, related to unlawful marketing. This is the first such letter to “adipose stem cell clinics”, after a long pause. Letter mentions 3 clinics. The Agency says that these clinics marketed adipose-derived cell therapies as minimally manipulated cell/tissue products. However, cell product, manufactured by clinics is more than minimally manipulated and does not fit definition of “homologous use”.

3. Mesenchymal stem cells in treatment of ALS – results of clinical trial
Israeli company BrainStorm Cell Therapeutics has published highly anticipated interim results of clinical trial, where autologous mesenchymal stem cells (MSC) were used in experimental therapy of patients with ALS.

Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale–Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression.
The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials.

There was a lot of excitement about these results in the mass media, however, it is too early to declare efficacy of MSC. The study was uncontrolled. Business analyst Adam Feuerstein, called public news release as “highly promotional”:

“Breakthrough,” “revolutionary” and “dramatic” were adjectives deployed by Brainstorm Cell Therapeutics (BCLI) in an email pitch inviting reporters to a press conference being held Monday morning.

A more honest description of the actual Brainstorm ALS study data would be recycled, inconclusive and highly promotional.

CIRM blog interviewed study’s principal investigator:

“I am optimistic that within the foreseeable future, we may provide a treatment to ALS patients that can slow down or stop the progression. I believe we are in the early stages of something new and revolutionary with this harvested stem cell infusion therapy. While this is absolutely by no means a cure, it is the first step in a long process in that direction.

Did public anticipated from “stem cell revolutions” only “slowing a progression”?

4. Design of new switch-on CAR T-cells
Spatiotemporal control and safety of therapeutic CAR T-cells is a very hot topic in cellular immunotherapy of cancer. This week, two more studies appeared online, which describe two strategies to design easily controlled switch-on CAR T-cells. The first study was done French biotech company Cellectis:

In this report, we showed that the hinge engineering approaches allowed to turn a T-cell endowed with an engineered CAR from an off-state to an on-state. By controlling the scFv presentation at the cell surface upon addition of the small molecule, our system allowed to further induce the cytolytic properties of the engineered T-cell. Overall, this non-lethal system offers the advantage of a “transient CAR T-cell” for safety while letting open the possibility of multiple specific cytotoxicity cycles using a small molecule drug.

The second study, performed by researchers from Scripps Institute and NCI, offers another switch-on strategy:

Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as “switch” molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a “universal” anti-FITC–directed CAR-T cell.

5. Donor-specific variability overrides cell type-specific variability in iPS cell generation
Very interesting study, which investigates potential root cases of genetic variability between iPS cell lines, was published in Stem Cell Reports. Turns out that genetic variability between iPS cell lines mainly explained by donor-to-donor variability, but not tissue source from the same donor:

Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.

6. More on automation of iPS cells production
The Scientist magazine posted a big piece on automation of iPS cell lines generation – Pluripotency Bots. This is very good overview of all recent efforts to robotization of iPS cell production, covering different systems from different centers and countries. Highly recommended!

7. More on synthetic logical cell sensors
Do you remember the most mindblowing study of the last year? Yes, implantable synthetic cytokine converter! Graduate student Dan Kramer wrote a good post on this technology on Scitable:

This work sets the stage for creating designer cell lines that could be used to treat other diseases that have biomarkers associated with them. Instilling Boolean logic into a cell, like the ‘AND’ gate, implies that biological engineering may be able to deal with complicated biological scenarios we may come across in the future.

Read everything about it!

8. Ups and downs of gene therapy companies
STAT news has a nice piece about recent news from gene therapy companies and their impact on a stock:

And this week the Maryland biotech company GenVec’s stock was sent spiraling down when enrollment of new patients in an early-stage trial testing its experimental gene therapy for hearing loss was halted. The reason: an independent monitoring board recommended a safety check.
To be sure, the news wasn’t entirely glum: Last week UniQure reported encouraging results from a small, early-stage study of patients with hemophilia.

9. New methods and protocols:
Generation of pituitary gland in self-organizing culture of human ES cells (Nat Commun)
CRISPR/Cas9‐induced disruption of gene expression in mouse embryonic brain (EMBO Rep)
Inter-batch differences in stem-cell derived neurons (Stem Cell Res)
iPS cell-derived allo- teratocarcinomas provoke immune rejection in mice (Sci Rep)
CD146/MCAM defines functionality of human bone marrow-derived MSC (Stem Cell Res Ther)
Differentiation of human iPS cells into smooth-muscle cells: two protocols (PLoS ONE)
Rapid conversion of human urine cells into functional neurons (Stem Cells Int)
Investigation of miRNA from human neural stem cell-derived exosomes (PLoS ONE)

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