Acceleration in iPS cells clinical applications!!

[lacazette]

Hey Joachim you're right, one of the issues was that not every iPSC lines was able to differentiate in what they want, so it was hardworking and cost expensive for large DP-induced production to be clinically applicable

But now with that combo Minerva/SendaiVirus iPSCs, the 'clonally restriction' problem is solved.

The other one was safety, Terskish was saying he needed 2 years and 5M for tumorigenicity in Feb 2015 but now:

-SendaiVirus enable iPSC reprogramming with 100% chromosomal damage free
-Minerva Biotech enable iPSC reprog in a Naive state that is more clean and safe
The combo of these two companies with their worlwide aggreement is great. As they said, they are disseminate their technology to anyone who work on iPSC treatment

And there's also from august month
- the spanish team, who found how dna damage could appear sometimes(during replication stress) and found easy and cheap methods to significantly reduce the potential risk
-helsinki's team who found how to replace Oct4 factor that was the most dangerous one
-Japanese researchers who found how to switch off the iPSCs after transplantation in case of any side effects : http://insights.bio/cell-and-gene-th...ing-mechanism/

"proving it is possible to erase iPSCs on demand and demonstrating that, if side effects were to appear in therapeutic use, it would be possible to eradicate problematic iPSCs.
Lead author, Hiromitsu Nakauchi commented, “This safeguard system can eliminate contaminating iPSCs and debulk tumors originated from iPSCs.It should be applicable to other cell therapies using iPSC-derived cells. The safeguard system can be an efficient and reliable approach to provide safety for future regenerative therapy and first-in-human cell therapy.”

So this summer progresses now provide a safe way for clinically iPSCs. Terskish's tumorigenicity issue timeline is significantly reduced now.

And it seems like terskish's team plan to take advantages of Japan's regulatory like others, cause on their official S&B page, they answered to just 5% of all the comments, but answered this particularly one from hellouser

"Thomas on February 4, 2015 10:25 pm
I would donate a lot of money ONLY if the clinical trials were done in Japan as regulations there allow for quick trials as well as a quick commercial release. USA and the FDA is a waste of time. We have one life to live and I am NOT willing to wait any longer for a treatment.

Reply 
Patrick Bartosch on February 13, 2015 2:32 pm

Dear Thomas,

Thank you very much for your comment and your interest in our research. We’ll keep your contact details on file and be in touch once this moves to a stage where we can discuss clinical trials and next steps.

Best,
Patrick Bartosch
Manager, Communications
Sanford-Burnham"


If terskish enter trial in a few months, that would mean the possibility of temp approval before 2018

But they are clearly not the only hope

-Tsuji Lab needed safe iPSCs to test his 3D hair germs on humans
-One of the 3 leader researchers of Sisheido hair center is working on growing hair with iPSCs
-Keio University project already grew 3D bioengineered hair on mouse, and needed safe iPSCs aswell to go further
-Regience aswell with some of the best jap researchers
-CHA biotech from Korea who are planning iPSCs trials and have a hair project
-Sung jan lin and his 3D hair from taiwan hospital
-Singapore/P&G agreement for iPSC's therapy
-and i don't talk about Us army/thomas darling, follica, Lauster, jahoda/cristiano, chinese ones and the others

that's a hell of competition, and iPSC safety from this summer will clearly have an impact for clinical trial. And the temp approval is in place to save us really sooner than the 5-7 years we would normally have to wait

@Jay, no answers dude, maybe my questions are too much detailed and they are suspicious ^^ But be sure i will post it here whenever i have something

[joachim]

Is it possible to have treatment in 1 to 2 years in Russia?

i don't think so. although the main researcher is russian, the work is done in florida at the sanford & burnham research center. they have to take it to japan for fastest release.

however, i could also imagine that when iPS knowledge gets more common, then other scientists around the world could theoretically replicate those procedures. it depends on how much know how is required to correctly create the DP cells from iPS. so far, the russian guy seems to be the most advanced. and he already announced that the next step is to try it on humans, but this step is at least 2 years away. only god knows why it takes that long.

but maybe those latest advancements in efficient iPS transformation could accelerate that next step a bit.

we need to get in contact with that russian scientist somehow. we need answers regarding the next steps.

[Hairismylife]

hey lacazette, this news is fantastic.
with that iPS toolkit they are now really able to kick back mature cells to a naive cell state, by only using a naturally occuring growth factor.
now it is cheap, efficient, and also safe.

i even think with this latest tweak, the russian scientist at sanford&burham can produce much more efficient DP cells from iPS (if you remember, they said efficiency so far is not so good, they had to discard some of their iPS lines).

i really hope they are all aware of those breakthrough and reprogramming technique. i'm dieing to hear a few words on further strategy from that russian scientist. now they have all the funding and all the techniques required. the only thing left is to create millions of DP cells and try to inject them into humans finally!
we are soooo close! and still far away from commercial use.
i could sleep so much better if they finally announce efficient iPS induced hair follicles in the lab.

this made my day.

Is it possible to have treatment in 1 to 2 years in Russia?

[JayM]

Hairismylife - It doesn't quite have that much to do with replicel. Unless sheishedo wan't to go down the path of using iPSC cells. It wont quicken up the process of them getting their RCH-01 to market anyway.

Lacazette - did you hear from anyone you contacted?

[joachim]

hey lacazette, this news is fantastic.
with that iPS toolkit they are now really able to kick back mature cells to a naive cell state, by only using a naturally occuring growth factor.
now it is cheap, efficient, and also safe.

i even think with this latest tweak, the russian scientist at sanford&burham can produce much more efficient DP cells from iPS (if you remember, they said efficiency so far is not so good, they had to discard some of their iPS lines).

i really hope they are all aware of those breakthrough and reprogramming technique. i'm dieing to hear a few words on further strategy from that russian scientist. now they have all the funding and all the techniques required. the only thing left is to create millions of DP cells and try to inject them into humans finally!
we are soooo close! and still far away from commercial use.
i could sleep so much better if they finally announce efficient iPS induced hair follicles in the lab.

this made my day.

[Hairismylife]

8 sept 2015, another team have found how reprogramming cells without Oct4 factor ( Oct4 is one of the 4 factor used for iPSC reprogramming, but according to the researchers was the most critical one for possible genome instability )

http://www.cell.com/stem-cell-report...%2900223-4.pdf

This activator in combination with guide RNAs targeted to the OCT4 promoter can be used to completely replace transgenic OCT4 in human cell reprogramming. Furthermore, we generated a chemically controllable dCas9 activator version by fusion with
the dihydrofolate reductase (DHFR) destabilization domain. Finally, we show that the destabilized dCas9 activator can be used to control
human pluripotent stem cell differentiation into endodermal lineages.

We demonstrate that the dCas9 activator can be used to replace transgenic OCT4 in human cell reprogramming and that human pluripotent cell differentiation can be induced by the activator in a TMP-dependent manner."

In one month of discoveries, genome stability during reprogramming process is now reality

If this can speed up Shiseido commercialization then it's a good news because even with this news I think the closest treatment is still Shiseido.

[lacazette]

8 sept 2015, another team have found how reprogramming cells without Oct4 factor ( Oct4 is one of the 4 factor used for iPSC reprogramming, but according to the researchers was the most critical one for possible genome instability )

http://www.cell.com/stem-cell-report...%2900223-4.pdf

This activator in combination with guide RNAs targeted to the OCT4 promoter can be used to completely replace transgenic OCT4 in human cell reprogramming. Furthermore, we generated a chemically controllable dCas9 activator version by fusion with
the dihydrofolate reductase (DHFR) destabilization domain. Finally, we show that the destabilized dCas9 activator can be used to control
human pluripotent stem cell differentiation into endodermal lineages.

We demonstrate that the dCas9 activator can be used to replace transgenic OCT4 in human cell reprogramming and that human pluripotent cell differentiation can be induced by the activator in a TMP-dependent manner."

In one month of discoveries, genome stability during reprogramming process is now reality

[lacazette]

Earlier state and chromosomal damage free iPS!

https://www.minervabio.com/news/minerva-granted-worldwide-license-to-sendai-virus-technology-for-stem-cell-generation/

WALTHAM, Massachusetts and Tsukuba, Ibaraki, Japan, August 27, 2015

Minerva Biotechnologies and ID Pharma Co., Ltd. (formerly DNAVEC) announced today that they have signed an agreement granting Minerva worldwide rights to use and commercialize their non-integrating Sendai virus vectors, together with Minerva’s proprietary technology, for generating Induced Pluripotent Stem (iPS) cells. Sendai virus enables delivery of genes into a host cell without permanently altering the cell’s chromosome, which is critical for stem cell therapies. Professor Shinya Yamanaka, MD, Ph.D., won the Nobel Prize for Medicine in 2012 for his discovery that four genes can reprogram an adult’s cell to go back in time to become that person’s own stem cell. Minerva Biotechnologies discovered a naturally occurring, primitive growth factor that continues this reprogramming to an even earlier, embryonic-like point called the ‘naïve’ state.

Scientists believe that because these earlier, naïve stem cells have a clean slate, they are more easily directed to develop into functional mature cells, which could be used for transplant. Naïve stem cells have several advantages over currently available stem cells (known as ‘primed’ state). These advantages are important for the future of stem cell therapies. Naïve stem cells do not yet have DNA methylation marks that commit the cells to certain developmental decisions. Additionally, naïve stem cells have a much higher cloning efficiency than primed state cells, which is critical for the realization of stem cell based gene therapies. Importantly, only naïve stem cells can contribute to the generation of chimeric animals. A futuristic stem cell therapy, which may not be that far off, is the generation of human-non-human chimeras that would express some human tissues or even entire human organs, for transplant.

Minerva’s proprietary primitive stem cell growth factor dramatically increases the efficiency of making human iPS cells, which greatly reduces the time and the cost of making iPS cells for research or for personalized stem cell banking. A problem that currently plagues the stem cell field is that although protocols have been devised that direct stem cells to mature into specific cell types, not every iPS cell line can mature into any cell type. As a consequence, researchers have to test many stem cell clones to determine which ones can form heart cells, which ones can form liver cells, etc. This problem is called ‘clonal restriction’ and would make personalized stem cell therapy impractical. In contrast, human iPS cells generated with Minerva’s technology are not clonally restricted; each of our human iPS cell clones has been demonstrated to have the ability to mature into heart cells, liver cells or neural cells. Minerva’s naïve state human iPS cells, or mature cells generated from, can be rapidly and inexpensively generated for use in basic research, drug toxicity testing or for personalized stem cell banking.

The agreement with ID Pharma Co., Ltd. allows Minerva to generate and sell naïve state human iPS cells as well as mature cells derived from them for research, drug toxicity testing and for personalized stem cell banking. Minerva Biotechnologies is the first company to generate human naïve state iPS cells using a single, naturally occurring human stem cell growth factor. Previous attempts to grow human stem cells in the elusive naïve state, which used ****tails of biochemical inhibitors and mouse growth factors, were prone to develop abnormal karyotype. Naïve stem cells generated with Minerva’s primitive growth factor have normal and stable karyotype. The generation of iPS cells from adult skin or blood cells does not involve the use of embryos and so does not invoke ethical issues.

“The agreement with ID Pharma Co., Ltd. provides Minerva with a powerful combination of technologies that will advance the study of basic science as well as accelerate the timeline to clinical applications of regenerative medicine,” said Dr. Cynthia Bamdad, CEO Minerva Biotechnologies. “We are very excited about our relationship with ID Pharma Co., Ltd. that allows us to disseminate our technology to others.”

“We have developed cell reprogramming kit based on our SeV vector technology as CytoTune®-iPS which could generate chromosomal damage free iPS cells easily with high efficiency. Now, the kit is well accepted in the field of stem cell research.” said Mr. Toyotaka Mori, Chairman of the board of ID Pharma Co., Ltd. “With the Minerva’s technology, we hope the iPS cells using CytoTune®-iPS technology will accelerate the development of regenerative medicine for unmet medical needs. That is very exciting.”

[lacazette]

Terskish representant was saying in june, that the team needed 1M to make the protocol for human use and 5M for the tumorigenicity issue during 2 years before enter clinical trial

-In july , jap researchers found how kill ALL the cells that don't reprogramming well and could become cancerigen= 1 problem resolved

- But even in the cells that reprogramming well with the traditionnal method, there's could little DNA mutations due to the reprogramming process. The risk is low according to the leader scientist of the riken center trial, but they halted it to study the mutations and found a new design for the reprogramming process:
In august the spanish team, found WHY these DNA damages occurs during the reprogramming process, but also found HOW significantly improve the DNA stability.

So the risk was low, now with this new technique, the risk is really low ( and as I said, it's just a matter of days before the same team or another lab in the world published the 2.0 method for 100% dna stability ( cause before that spanish team discovery, no one knew why and when this DNA damage occur (replication stress), so now the hundreds of iPSCs labs can work on it, so believe me the 2.0 method is for really soon

And last but not least:
-September 3, researchers have found a way for that after the transplantation of iPSCs in therapic use, if there is side effects that appears with these cells, they can eliminate all the iPSCs-derived in the patient !! (just by delivering the specific drug then)

"This demonstrates that if side effects were to appear in therapeutic use, it would be possible to eliminate the iPSC-derived T-cells in the patient.

This research provides a means to control any potential side effects that might occur as a result of the iPSC-derived T-cell therapy. It greatly advances the possibility of safe and effective T-cell therapies.

Nakauchi said, “This safety mechanism can also be applied to other iPSC-derived therapies.”
https://<br /> <br /> http://www.asi...afe-icaspase9/


So in one summer, if you combined these discoveries, we're about to reach almost 100% safety
it's exactly what Terskish team since january had to study and resolved before enter trial. So their 2 years timeline is logically really lowered now
And I let you imagine what's goin on in Japan

Sounds good guys, in just 2 months we approached the 100% safety unlike before. The speed of discovery in iPSC aera these last weeks is so fast, it's just a matter of days before 100% safety and so even more large expansion of clinical iPSC based therapy

[TJT]

Not about hair area, but for every kind of iPSC treatments, the first ever ipsc treatment was done in riken center in a woman with macular disease and she is doing well, they then move on second patient but they found dna mutations in some of the reprogrammed cells, and even if the leader researcher said that the risk was low for these mutations turn dangerous, they halted the expansion of the trial to study these mutations and to saw if they came from the patient's disease or the reprogramming process. then they confirmed that the reprogramming process was in fault

https://www.ipscell.com/2015/07/firstipscstop/

http://www.signalsblog.ca/the-waiting-game-first-human-ipsc-clinical-trial-on-hold/

"One patient was transplanted in September 2014 with their own IPSC-derived retinal pigment epithelial cells (using an innovative RPE sheet, see image) for treatment of macular degeneration.

The study then moved on to a possible second patient, whose IPSC did not pass a genomic validation step. Reportedly, these IPSC contained a mutation, potentially in a known oncogene, which is a serious concern. Thus, the team decided to at least temporarily suspend the trial pending a possible redesign. The new plan could involve a change in how the IPSC are produced.


"Initially, the nature of these mutations was unclear. In a series of comments on the original blog post, Dr. Takahashi explains that a total of six mutations were found in iPSCs prior to transplantation into a second patient. These mutations were not present in the genome of the patient, indicating that they arose during the reprogramming process. Dr. Takahashi maintains that the likelihood of tumour formation due to these mutations is low."

"The hope now is that further study of the mutations in the RIKEN iPSCs will help us to refine the reprogramming process to avoid future pitfalls"


So it's exactly what the spanish team resolved They found the origin and when this Dna damage occurs during the reprogramming process (replication stress) and not only that, they found an easy way to reduce it significantly, that every lab in the world could use and work on.


Dr. Knoepfler (stem cell researcher) was saying on his blog that if that halted trial is coming back in the game , it would be the major step forward for every iPSC therapy.

So the discovery of the spanish clearly reduce the timelines, and Im sure it will go even faster, cause now that they found the origin of these mutations and some easy ways to reduce it, every ipsc labs can work on it, so the 2.0 method for 100% Dna stability will be published in a few days, IMO

Let's ask the researchers working on iPSC themselves to confirm, but everything I read was that the large expansion of iPSCs trials was moving slow just because of the fear of these possible dna mutations

Would be interesting to find out how this affects Tsuji labs, because I think their neogenesis approach is based on iPSCs.

[lacazette]

I love your optimism, but this sounds like pure speculation. Do you have any information from Shiseido or any other leading-edge hair restoration research labs to back up your claim that this changes or strengthens their timeline?

Not about hair area, but for every kind of iPSC treatments, the first ever ipsc treatment was done in riken center in a woman with macular disease and she is doing well, they then move on second patient but they found dna mutations in some of the reprogrammed cells, and even if the leader researcher said that the risk was low for these mutations turn dangerous, they halted the expansion of the trial to study these mutations and to saw if they came from the patient's disease or the reprogramming process. then they confirmed that the reprogramming process was in fault

https://www.ipscell.com/2015/07/firstipscstop/

http://www.signalsblog.ca/the-waiting-game-first-human-ipsc-clinical-trial-on-hold/

"One patient was transplanted in September 2014 with their own IPSC-derived retinal pigment epithelial cells (using an innovative RPE sheet, see image) for treatment of macular degeneration.

The study then moved on to a possible second patient, whose IPSC did not pass a genomic validation step. Reportedly, these IPSC contained a mutation, potentially in a known oncogene, which is a serious concern. Thus, the team decided to at least temporarily suspend the trial pending a possible redesign. The new plan could involve a change in how the IPSC are produced.


"Initially, the nature of these mutations was unclear. In a series of comments on the original blog post, Dr. Takahashi explains that a total of six mutations were found in iPSCs prior to transplantation into a second patient. These mutations were not present in the genome of the patient, indicating that they arose during the reprogramming process. Dr. Takahashi maintains that the likelihood of tumour formation due to these mutations is low."

"The hope now is that further study of the mutations in the RIKEN iPSCs will help us to refine the reprogramming process to avoid future pitfalls"


So it's exactly what the spanish team resolved They found the origin and when this Dna damage occurs during the reprogramming process (replication stress) and not only that, they found an easy way to reduce it significantly, that every lab in the world could use and work on.


Dr. Knoepfler (stem cell researcher) was saying on his blog that if that halted trial is coming back in the game , it would be the major step forward for every iPSC therapy.

So the discovery of the spanish clearly reduce the timelines, and Im sure it will go even faster, cause now that they found the origin of these mutations and some easy ways to reduce it, every ipsc labs can work on it, so the 2.0 method for 100% Dna stability will be published in a few days, IMO

Let's ask the researchers working on iPSC themselves to confirm, but everything I read was that the large expansion of iPSCs trials was moving slow just because of the fear of these possible dna mutations

[TJT]

Sisheido, regience, sung jan lin and all the others in the world could now planning for government authorisation for iPSC human trial testing in the coming weeks/months!! For the septics who don't believe it , just ask them directly (company/researchers) how these two breakthroughs of the summer change everything in term of timeline

I love your optimism, but this sounds like pure speculation. Do you have any information from Shiseido or any other leading-edge hair restoration research labs to back up your claim that this changes or strengthens their timeline?

[JayM]

Yeh I just want to get some inside knowledge, not really of the companies just what the industry is feeling kind of thing.

[lacazette]

I hope you're right lacazette I wonder if I try to contact some of these guys and ask them what this means ect. Might say I write a blog or something :')

Yes I will try too jay, but i will try also with all the ones who work on iPSC treatment for hair (or even for other diseases). Since this summer, they have the easy tools to make tumor free iPSCs, and iPSCs with so much less DNA damage. The two major issues overcomed, human trial autorisation is now becoming a possibility unlike before, hope they will confirm that

[JayM]

but the definitive approval don't matter for us who are motivated to have the procedure done in 2017-18 under the temp approval
the only thing is that we will have to pay for something that don't have long safety data (just 12/16months data) and the guaranteed for 100% effectiveness ( we will have the hair we want of course, but there will be no data to know if those hair will last more than 3,5,10 years, etc. We will have to sign papers to confirm that we are aware of these two parameters and that it's kinda like a real life person to person clinical trial.

So yes the 5 years between the two approval is a normal process to complete the trial phases, to confirm the long term safety and long term effectiveness of the treatment.
The recent temp approval system in japan is a benediction for the ones of us who don't want to wait many years and are aware of the risks, without it we would be condamned to wait so much time.

Who will pay to be a guinea pig in some months? I do :d

take my money!