Acceleration in iPS cells clinical applications!!

[failly]

Nucleoside Supplementation Reduces Genomic Damage in Induced Pluripotent Stem Cells

"Nucleoside Supplementation Reduces Genomic Damage in Induced Pluripotent Stem Cells"

14 september 2015

"Spanish researchers have described a method to reduce the amount of genomic damage incurred during the process that transforms mature adult cells into induced pluripotent stem cells (iPSC), thereby making them potentially useful for biomedical applications.

The reasons behind the genomic instability observed in iPSCs remain mostly unknown. Investigators at the Spanish National Cancer Research Center (Madrid, Spain; www.cnio.es) recently suggested that this genomic instability was similar to the phenomenon of oncogene-induced replication stress, and that the expression of reprogramming factors induced replication stress.

Replication stress is defined as slowing or stalling in DNA replication fork progression. It arises from many different sources, which are considered as replication barriers such as telomeres, repetitive sequences, DNA lesions and misincorporation of ribonucleotides, secondary DNA structures, DNA–RNA hybrids, dormant replication origins, collisions between replication and transcription complexes, hypo-acetylation and compaction of chromatin, early-replicating fragile sites (ERFSs) and common fragile sites (CFSs). Overexpression or constitutive activation of oncogenes has been cited as an emerging source of replication stress.

The Spanish investigators reported in the August 21, 2015, online edition of the journal Nature Communications that increasing the levels of the protein checkpoint kinase 1 (CHK1) reduced reprogramming-induced replication stress and increased the efficiency of iPSC generation. Similarly, nucleoside supplementation during reprogramming reduced the load of DNA damage and genomic rearrangements during the iPSC generation process. The data revealed that lowering replication stress during reprogramming, genetically or chemically, provided a simple strategy to reduce genomic instability in mouse and human iPSCs.

First author Dr. Sergio Ruiz, a researcher in the genomic instability group at the Spanish National Cancer Research Center, said, "Based on previous research performed by the group, we knew that an additional input of nucleoside reduces replication stress, probably by facilitating the successful replication of DNA as it increases the rate of cell division during the reprogramming process."

[mikes23]

I believe we are moving alot faster towards a cure then we ever were before but still seems there are issues with ips cells

http://www.forbes.com/sites/emilymullin/2015/08/20/scientists-claim-fix-to-stem-cell-rejection-problem/

"Earlier this month,*New Scientist reported*that the Japanese trial has been halted after genetic mutations were detected in the cells of the second trial participant. The first subject to receive an experimental iPS cell treatment, a 70-year-old woman, is reportedly healthy."

I also came across this from the same article

"Still, Xu acknowledges that there is yet another hurdle to overcome for the stem cell therapy to be successful. “Macular degeneration-associated inflammation can also kill cells transplanted into the lesion,” Xu said. “This would be another immune-related challenge for iPS cell-based therapy.”

I know it's not talking about hair loss, but I wonder if the inflammation caused by hair loss is also killing these ips cells that are being transplanted?

none the less, the article still shows how we are progressing

"Now, a team of scientists headed by biologists at UC San Diego has discovered how induced pluripotent stem (iPS) cells, which are derived from an individual’s own cells, could be programmed to avoid rejection from the immune system."

I think ips cells will help the medical field greatly but I still think lab grown follicles are our best chance.

Here is a good article about 3d printing. Stuff like this may be able to help dr lauster create a terminal follicle.

http://arstechnica.com/science/2015/09/dna-used-as-velcro-to-form-cells-into-3d-structures/

"One of the great hopes for stem cells is that they'll allow us to eventually replace injured or damaged tissues. But there's a big gap between the cells of stem cells and anything resembling an organ. Organs are complex, three-dimensional structures populated by multiple cell types. Getting a bunch of cells to form these structures is a significant challenge."

"One idea has been to use 3D printers. With multiple print-heads and a protein polymer gel, it's possible to construct a rough approximation of the structure of a mature organ. Now, a team of California scientists has come up with an interesting alternative: use DNA as a sort of cellular velcro to get cells to stick to each other and form a complex, three-dimensional tissue."


I also emailed Dr lauster to see if they would be attending the hair loss conference. But Desmond if you have time could you get in contact with them? I'm thinking if they don't go to the Conference then they might be done with lab follicles. So I'm hoping you could rule that out by asking them. Or they might have solved it and don't want to give out to much information to the competition. I remember you saying it seemed like they were holding something back from you. I would email him and ask but I figured, one if we all keep emailing him he will stop responding....two, you are already familiar with him, so he might reveal more information to you. It just seems strange that one of the top hairloss doctors wouldn't have his team attending the world hairloss conference.

[Renee]

I agree with mike! I emailed them a month ago about the progress on hair loss research. I received an automatic email response from their CEO who said " I am attending a conference and will respond to emails with a delay." I never heard anything back from them.

[lacazette]

Joachim and Desmond, thank you guys but i don't really deserve, key words and google are the one to be grateful hehe


Hey mikes, yep that trial is really important, it has been halted in June, but that's why we saw so many breaktroughs this summer on the particular area of "reprogramming DNA damage free iPSCS" (as every iPSCs team over the world work on this last major issue)

At that time they found a few mutations in some cells ( even if not dangerous according to lead trial Phd Dr. Masayo Takahashi ) they halted and didn't go for the second patient to first,investigate if it was coming from the patient's disease or if it was due to the reprogramming process. Then they confirm that it was the last one. According to Dr.Takahashi, they were making a redesign of how iPSCs are produced and there are also adjustments and changes in japan's regulations in this area, detailed genetic analysis of ips lines before transplant, etc

And according to Dr Knoepfler a stem cell researcher, when they will enter the trial again, it will be the major step forward for other iPSCs clinical

And i think it moves well, Dr Takahashi will receive today the inaugural Ogawa-Yamanaka Stem Cell Prize at the Gladstone Institutes in San Francisco

http://www.news-medical.net/news/20150910/Masayo-Takahashi-awarded-inaugural-Ogawa-Yamanaka-Stem-Cell-Prize.aspx

Dr. Takahashi was awarded the prize for her trailblazing work leading the first clinical trial to use induced pluripotent stem (iPS) cells in humans.

"It is extremely gratifying to see iPS cell technology applied in humans only eight years after its discovery," says Shinya Yamanaka, MD, PhD "I applaud Dr. Takahashi's pioneering work to advance stem cell technology and help cure ocular diseases." Dr. Yamanaka, who is the director of the Center for iPS Research and Application (CiRA) at Kyoto University, won the Nobel Prize in 2012 for his discovery of iPS cells.

George Daley, MD, PhD, professor of hematology/oncology and director of the Stem Cell Transplantation Program at Boston Children's Hospital, says, "By confronting and ultimately solving the many regulatory challenges of a first-in-human trial, Dr. Takahashi has paved the way for all of us in the stem cell community to recognize the promise of iPS cells."

The first surgery was successfully performed in September 2014 using retinal tissue Dr. Takahashi created from the patient's own iPS cells. Prior to moving the study to a second patient, Dr. Takahashi chose to delay the trial as part of a safety validation step and in consideration of anticipated regulatory changes to iPS cell research in Japan. This demonstrates an appropriate degree of caution applied in such research and highlights the rigor displayed by this year's recipient.

"As both a physician and a scientist, Dr. Takahashi embodies the ideal recipient because her work brings cellular reprogramming to patients," says Gladstone president R. Sanders Williams, MD. "Mr. Ogawa's visionary support of translational stem cell research will help encourage and accelerate the progression of the field."

(ps: they say the ceremony will be live streaming, maybe we could learn something)

I aslo read CIRA annonced planning enter iPSCs trials for various serious diseases this coming year, aswell as CHA Korea in collaboration with Japan hospitals, and maybe others of course
So i think this summer progresses on reprogramming make his job, and DNA safety, new regulations, etc are currently in the process to be overcomed
let's see if Dr takahashi will say something tonight about what's goin on now

For the lab grown follicles you talked about Mike, on the japan tv show about Shiseido/replicel, it is explained how Dr Tsuji already grow lab hair, but that with a skin biopsie ( to take the cells needed) , he can grow just 1 hair or so, when we would need more than 10000. And so that the solution is iPSCs to have unlimited cells
differents researchers already how to grow lab hair with various kind of method, but unfortunatly the problem is the limited cells number we have

As you posted, there's unreal progress in 3D bio engineering/bioprinting, for large real life clinical application and in our case the tools to create functionnal lab hair but the last problem is that we need that unlimited source of our own cells as a source to create a large number of hair

And we will have soon, Minerva/SendaiVector + the robot sell by NYSCF = almost 100% of the iPSCs problems solved (and if you add the breakthroughs in august from the spanish team, the helsinki one, etc..it is going fast) It's no surprising as it's the n'1 problem in iPSC area now,and there's hundreds of the best team in the world working on it. and so they working for us hair loss sufferers lol cause we know how to grow hair, but we just need iPSCs to grow unlimited hair
so it's the whole world science now who work to solve the last issue, we , hair loss sufferers need to overcomed to make a hair therapy possible. So in fact it's no more 50 researchers who work for our problem, but 10000+ indirectly ^^ it will move fast as we are seeing it til' july, august, sept. Im confident let's see how it goes in the comin' weeks


I'll put the link of Yamanaka prize stream tonight, Dr Takahashi will talk about her trial

[nameless]

Joachim and Desmond, thank you guys but i don't really deserve, key words and google are the one to be grateful hehe


Hey mikes, yep that trial is really important, it has been halted in June, but that's why we saw so many breaktroughs this summer on the particular area of "reprogramming DNA damage free iPSCS" (as every iPSCs team over the world work on this last major issue)

At that time they found a few mutations in some cells ( even if not dangerous according to lead trial Phd Dr. Masayo Takahashi ) they halted and didn't go for the second patient to first,investigate if it was coming from the patient's disease or if it was due to the reprogramming process. Then they confirm that it was the last one. According to Dr.Takahashi, they were making a redesign of how iPSCs are produced and there are also adjustments and changes in japan's regulations in this area, detailed genetic analysis of ips lines before transplant, etc

And according to Dr Knoepfler a stem cell researcher, when they will enter the trial again, it will be the major step forward for other iPSCs clinical

Any idea when they will re-enter the trial? I wish they would implant the 2nd patient soon.

[barfacan]

We're still a loooooong way from safe, practical human application. It's nice to get your hopes up, but it sucks when they come crashing down after years of abandoned treatment research

[Swooping]

Lacazette you are a beast at digging up information! Great job.

Some promising therapies are coming our way, that's for sure. Hopefully it will be as quick as possible.

[lacazette]

Hey nameless, don't know for the moment, they are choosing the best way for reprogramming,etc and that lead to new regulations tools to take in place. so since this summer it should be a matter of weeks. Aswell as CIRA and cha who annouced planning few trials this year

@barfacan do you read the last pages man? I thinked not based on your other posts safety and practical human application is making his road right now. It's the commercialisation that is far away ( though the temp approval makes it not that far)

@Swooping Thanks bro i hope aswell that breaktroughs comes out as fast as these last 2 months. 100% Safety is the last issue that slow everything, and it's being overcomed now (if not already), the science world work on it so just a matter of days unlike hairloss news


My bad i totally forgot the livestream of Dr Takahashi last night due to champions league

but they say the podcast will be available online today at 11:30 AM Pacific Daylight Time

[lacazette]

Some quotes from Gladstone Institutes twitter during Dr Takahashi award, I like what i read:

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
The first patient to receive a transplant with iPSC is healthy and doing well, with no adverse events #OgawaYamanaka

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
The next step is to use iPSC from #stemcell banks in order to conduct more surgeries faster and cheaper #OgawaYamanaka

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
Dr. Takahashi's groundbreaking work conducting first transplant using iPSC in retina paves way for future iPSC surgeries for other diseases

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
Japan has created a new law to expedite translational research using #stemcells, but emphasis is still on safety #OgawaYamanaka

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
Safety requirements should be consistent for #stemcell research: right protocols ensure tumors don't form, even w/ genetic changes in cells

Gladstone Institutes @GladstoneLabs 16 hil y a 16 heures
For regenerative medicine to succeed, science, regulation, and industry must work together for the best of the patient #OgawaYamanaka

[JayM]

“As of now, autologous would not be a feasible way of providing wide level clinical therapy,” says CiRA spokesperson Peter Karagiannis. “At the experimental level it’s fine, but if it’s going to be mass produced or industrialized, it has to be allogeneic.”

This isn't so good for us however. In Asia they have all the stem cell lines to be able to do this. However in the west we don't and to be able to set up the amount of stem cell lines needed to cover the much more vast genetic differences wont be worth the cost - until stem cell and iPSC therapies take off.

This is what i keep mentioning to people who think shiseido will be a cure with iPSC's.

[lacazette]

Hey jay , with NYSCF robot , and ameliorations in this kind of robot , large autologous should still be feasible for a big company, less cheaper and less faster expansion than allogeneic of course but as NYSCF explained, one machine can make thousands of iPSCs from a patient specific stem cells

Though autologous don't really matter as allogeneic ipscs use will also be for us don't worry dude. This kind of robot from NYSCF will do the job:

http://nyscf.org/research

* The NYSCF Global Stem Cell Array

Building a bank of 2,500 stem cell lines representing the genetic diversity of the United States and the world.

This revolutionary global resource will equalize access for safe and effective medicine for EVERYBODY including underserved populations.

This critical step between animal testing and human testing will transform drug development by cutting down years of time and billions of dollars currently spent on human clinical trials and ultimately accelerating the approval of new drugs and therapies by the FDA.

Bone Regeneration: NYSCF is using iPS cells and embryonic stem cells to produce personalized human bone grafts that will be used to treat and repair damaged bones. These bone grafts will be patient-specific, avoiding immune rejection. This will be the first time we will have vascularized bone grafts that are engineered using human cells.

Also regarding the ermegence of stem cells banks

September 1, 2015

San Francisco, CA –The largest publicly available stem cell bank in the world is now open for business. In September the bank is offering the first 300 different stem cell lines for researchers interested in gaining a deeper understanding of, and developing treatments. CIRM has teamed up with the Coriell Institute and Cellular Dynamics International (CDI) to open what will be the world’s largest publically available stem cell bank. It officially opened today. In September the Bank will have 300 cell lines available for purchase but plans to increase that to 750 by February 2016.

-Sept 8,CiRA, Hitachi to produce, store iPS cells from healthy donors for research

To advance stem cell research, Kyoto University's Center for iPS Cell Research and Application (CiRA) and Hitachi Ltd. will be producing induced pluripotent stem (iPS) cells from healthy subjects and storing them in a cell bank.

CiRA and Hitachi said on Sept. 7 that they will be producing iPS cells from blood donated by healthy subjects to store at the Riken BioResource Center's Cell Bank together with anonymized data of the donors' medical records.

Jay, I'm not 100% sure but I think with one iPSC line we can make an unlimited amount of cells (derived dermal papilla cells for exemple) , so the match donor question will not be that complicated. robots will do the job, for large banking, and then to find matches
Apparently 2500 lines represent the world genetic diversity , I though it was much higher than that

[joachim]

it's crazy if you think about it. the discovery of iPS cells happened only 9 years ago, in 2006. before that discovery scientists had no clue that mature cells could be kicked back to a stem cell state and then again differentiated into any other cell type. it changed the knowledge of how cells work among scientists. and only 9 years after that mankind-changing discovery, we have the first human application seen in this woman, with many more applications for different diseases to follow. i believe we will see a firework of iPS news in the upcoming months and years. all that pre-work for other diseases will highly help establishing a hairloss treatment when all pieces come together.
that said, thinking that a real hairloss cure is always 10years away, is just ridiculous.
with japan's fast tracking i think, everything is possible, and a cure within the next 5 years is not unlikely.

[lacazette]

totally agree Joachim, progress is going exponential, we will be surprise in the coming years and not only for hair but for our health and people we care about deadly diseases


Some quotes from takahashi before summer:

Some mutations were detected in the iPS cell-derived RPE product, prepared for the second patient.
“The mutated genes were not driver genes for tumor formation,” wrote Takahashi

Although the mutations were identified before transplanting cells into the second patient, and the mutations may have contributed to RIKEN’s decision not to treat, the main reason not to go ahead with the trial was because of a “regulatory change,” says Takahashi.

there is no guidance in new regulation about “allowable” level of mutations and methods of their detection in iPS cell products:

… there is no regulation with which medical professionals are obligated to check gene modification for organ transplantation, mesenchymal stem cell injections or autologous cell therapy.
The fact remains that we do not have clear guidelines today on which the whole community can reach a consensus that “the second” RPE cells are safe enough for implantation .

As a pioneer of iPS cell clinical application, Riken took the responsible decision not to rush ahead with the second patient’s RPE cells, which could potentially damage the whole field of regenerative medicine.

Although therefore, the cells were widely thought to be safe to use, after careful consideration, they made the decision that they would not implant another autologous cell sheet until such guidelines could be officially authorized.
They are now coordinating the discussions at the Ministry of Education, Culture, Sports, Science, and Technology, and also at the Ministry of Health, Labor and Welfare to carefully discuss these issues with key opinion leaders in the field including government officials, regulatory experts, scientists and toxicologists.

RIKEN is moving forward with allo- iPS cell-derived RPE. Moving together with CiRA. Well characterized partially matched lines with “safety clearance” by rigorous QC testing.

[Swooping]

Excellent presentation by Ohyama about iPS cells. Worth a repost imo! Exciting.

[lacazette]

http://www.moorfields.nhs.uk/news/new-trial-wet-amd

http://blog.cirm.ca.gov/2015/10/02/stem-cell-stories-that-caught-our-eye-better-heart-muscle-first-patient-with-eye-cell-patch-brain-cross-talk-and-gut-bugs/

London Monday 28 September: A pioneering trial of a new treatment derived from stem cells for people with ‘wet’ age-related macular degeneration (AMD) has commenced at Moorfields Eye Hospital following a successful operation on a patient.

Doctors at the Moorfields Eye Hospital in London have used specialized eye cells derived from embryonic stem cells and grown on a synthetic scaffold to try to reverse blindness caused by age-related macular degeneration(AMD). Prior clinical trials have injected similar cells but without the supporting structure of the patch to hold them in place.

Also, prior trials have aimed to halt the progressive loss of vision in the dry form of macular degeneration. This trial is trying to reverse damage already done by the wet form of AMD. Each of the groups use embryonic stem cells and first mature the cells into a type of cell found in the back of the eye’s retina, retinal pigmented epithelium (RPE) cells.

The first surgery was successfully performed on a patient last month and there have been no complications to date. The patient wishes to remain anonymous, but the team hope to determine her outcome in terms of initial visual recovery by early December (2015).

“The reason we are very excited is that we have been able to create these very specific cells and we have been able to transfer them to the patient,” lead researcher Lyndon Da Cruz told a writer for the Huffington Post. “It’s the combination of being able to create the cells that are missing and demonstrate that we can safely transplant them.”

CIRM funds a team at the University of Southern California and the University of California, Santa Barbara that has collaborated with the London team and plans to use a similar patch system on a trial set to begin in the next few weeks.

“We are delighted to be the site for this very exciting new clinical trial in stem cell therapy, which has the potential to give hope and make such a difference to the lives of people with blinding retinal conditions,”.

https://www.ipscell.com/tag/london-project-to-cure-blindness/

We’ve been hearing a lot this week about an important new clinical study for macular degeneration in the UK. This team is using retinal pigmented epithelial cells (RPEs) made from embryonic stem cells (ESC). They are now testing safety.
There’s real reason for excitement in this area more broadly and that context is important to include, but many newspaper articles haven’t.

For instance, Ocata Therapeutics is doing very similar clinical work and is already years into its FDA-approved clinical trials for macular degeneration using RPEs made from ESC. So far that work has proceeded really well without safety concerns and with hints of efficacy. Also the clinical study in Japan for macular degeneration using IPS cells, while at present on hold, will likely start up again in a new iteration later this year or more likely in early 2016."


it's the same protocol of different hair cure strategies on the making: make the right cells, grow them on a scaffold to then transplant them
so let's all cross our fingers that everything goes well in this trial in term of safety ( with the stemcells post transplant, it's ESCs so it's similar of iPSCs but without the reprogramming process so more safe but still with safety concerns unanswered, and really hope for safety and any kind of problems for using the scaffold thing as we will need that)
Cause if big safety problems comes out, it will add maaany months/years on other regenerative therapies timelines