Cells Weekly October 11, 2015 – stemcellassays.com

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. Gene therapy of eye disease succeeded in Phase 3 trialThis week, US-based gene therapy company Spark Therapeutics reported positive data from their Phase 3 trial in inherited retinal dystrophies.

We saw substantial restoration of vision in patients who were progressing toward complete blindness, said Albert M. Maguire, MD, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania. The majority of the subjects given SPK-RPE65 derived the maximum possible benefit that we could measure on the primary visual function test, and this impressive effect was confirmed by a parallel improvement in retinal sensitivity. If approved, SPK-RPE65 should have a positive, meaningful impact on the lives of patients with this debilitating condition.

Sparks results are remarkable, because this is a first success in Phase 3 gene therapy trials under FDA jurisdiction. It was a pivotal trial before application to FDA for approval their gene therapy drug on a market:

Based on these results, Spark intends to file a Biologics License Application with the U.S. Food and Drug Administration in 2016 as the first step in executing its global regulatory and commercialization strategy.

Hopefully, US will get the first approved gene therapy drug on a market next year.As a follow-up from this release, yesterday the company reported that positive effects persist for 3 years:

Since the final-stage trial only has tracked patients for a year, Spark also presented at the conference the longer-term data on patients who had been treated in an earlier study and were available for follow-up. Out of eight patients who would have qualified for the final-stage trial, all seven who were available for follow-up after three years sustained their improvement

2. CRISPR gene editing used to create humanized organs in pigsA group of researchers, led by Harvards Professor George Church, reported today in Science a technique of simultaneous gene edit of 62 porcine endogenous retrovirus genes in kidney cell line. Excerpt from Science Insider:

Church believes the new work could revive the idea of xenotransplantation, as the use of animal organs in people is called. Basically, this whole field has been in the doldrums for 15 years, he says. Theres been kind of a few true believers that had it on life support. But I think this changes the game completely.Church believes the new work could revive the idea of xenotransplantation, as the use of animal organs in people is called. Basically, this whole field has been in the doldrums for 15 years, he says. Theres been kind of a few true believers that had it on life support. But I think this changes the game completely.That cells even survived having their DNA hacked up in 62 places is remarkable, says molecular biologist Jennifer Doudna of the University of California, Berkeley, one of the original developers of CRISPR.

Wyss Institute press release called this technique an explosive leap forward in CRISPR capability. It is definitely an advance in CRISPR-based techniques, but its potential yet to be tested in vivo experiments.

3. Advances in growing kidneys and intestinesAustralian scientists reported a technique for growing the most complete version of human kidney in vitro from iPS cells. From Nature commentary:

It is vital to emphasize that the result of this process is not a kidney, but an organoid. The structures fine-scale tissue organization is realistic, but it does not adopt the macro-scale organization of a whole kidney. For example, it is not plumbed into a waste drain, and it lacks large-scale features that are crucial for kidney function, such as a urine-concentrating medulla region containing mature forms of structures called loops of Henle and radially arranged collecting ducts. There is a long way to go until clinically useful transplantable kidneys can be engineered, but Takasato and colleagues protocol is a valuable step in the right direction.

The most advanced model of whole human intestine was recently reported by David Hackams group. The most important feature of their model is addition of normal micro-flora bacteria into the bioengineered organ:

Intestinal progenitor cells from mice or humans were cultured with myofibroblasts, macrophages and/or bacteria, and evaluated in mice via omental implantation. Mucosal regeneration was evaluated in dogs after rectal mucosectomy followed by scaffold implantation.

4. Immunogenicity of iPS cell derivatives determined by immune microenvironmentSome studies showed that auto- or syngenic cells, derived from iPS cells are immunogenic. New short study, published online in Stem Cells, confirms previous findings and explains this phenomenon by lack or abundance of dentritic cells in local tissue site where iPS cell-derived cells implanted:

While some studies conclude that certain cells derived from iPSCs are immunogenic in syngenic recipients when transplanted subcutaneously, one study has shown that various cells differentiated from iPSCs are not immunogenic when transplanted under kidney capsule. To resolve this critical issue on the safety of iPSCbased therapy, we now demonstrate that kidney capsule lacks functional dendritic cells (DCs) and thus prevents Tdependent immune responses to minor antigens expressed by iPSC derivatives.

5. Animal serum in MSC translationDemocratizing Cell Technologies blog posted a great piece on use and regulation of animal serum in clinical production of mesenchymal stromal cells (MSC):

While small-scale clinical studies can be conducted with a single batch of FBS, both supply chain and performance challenges increase when attempting to scale up production for large-scale clinical trials and commercial cell manufacturing. The ability to reserve large lots of batch-tested FBS is needed as hMSC-based therapies become commercialized.

6. Pricing of gene therapy drugsThe Signals blog has very interesting post on the first prescription of Glybera and on pricing of gene therapy drugs:

September 2015 has been an historic month for regenerative medicine. For the first time ever in the Western world, a prescription has been issued for a gene therapy, Glybera. At the ESGCT and FSGT Collaborative Congress, Helsinki, this news was welcomed and spurred discussion on broader challenges in the gene therapy field.When discussing gene therapies, the question Is it worth it? is often muttered. At such a high cost, can these products really be justified? Is it worth investing in what has proven historically to be a risky area? If there is a clear patient need addressed with appropriate business models, effective management, and exceptional science demonstrating clear, material results, this question will go away.

As gene therapy drugs are getting close to marketing approvals, a lot of discussions are happening on pricing. Id encourage you to discuss it on blogs or twitter!

7. Chinese company criticized for plans to market gene-modified petsLast week, Nature reported about plans of Chinese genomic sequencing giant BGI to market gene-edited micropigs as pets. The criticism of BGI plans in western world is getting bigger and bigger. From the Guardian:

But the idea has horrified animal welfare groups, and some scientists. The idea is completely unacceptable, Dr Penny Hawkins, head of the RSPCAs research animals department, told the Observer. In the past, pets have been bred by selecting animals, generation by generation, to produce a desired trait. Inducing a massive change in one go risks creating animals that suffer all sorts of horrific impairments.The RSPCA is concerned that the technique risks creating animals that may have long-term health and welfare problems that are difficult to predict. It is also worried that pet owners will not be able to properly care for or monitor the animals.

from LA Times:

Kenneth Bondioli, a professor of animal sciences at Louisiana State University, said BGIs gene-edited micro pigs would need to be evaluated to see if they develop healthily and to determine whether they would could harm the environment or other livestock if they were released or escaped. It is unclear whether BGI intends to offer its pigs for sale outside China, but if Americans wanted them, U.S. regulators would have to determine whether they could be imported.

If these and other questions are addressed, the fact that they are gene-edited is irrelevant, Bondioli said.

8. New methods and protocols:CUBIC protocols for whole-brain and whole-body clearing (Nature Protocols)Reprogramming via bacterial injection of defined transcription factors (Sci Reports)Human iPS cell-derived insulin producing cells form vascularized organoids (PLoS ONE)Generation of kidney organoids from human pluripotent stem cells (Protocol Exchange)Rapid assay of stem cell functionality and potency using electric cell-substrate impedance sensing (Stem Cell Res Ther)Reprogramming of mouse fibroblasts into iPSCs (Protocol Exchange)3D hydrogel scaffolds for articular chondrocyte culture (JoVE)Rapid generation of hepatocyte-like cells from adipose-derived stem cells (Stem Cell Res Ther)Isolation of mouse bone marrow-derived monocytes (Protocol Exchange)

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Cells Weekly October 11, 2015 - stemcellassays.com