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An Eye for Stem Cells

Japanese researchers are launching an iPS cell trial for an untreatable eye disease, challenging ongoing embryonic stem cell trials.

By | December 1, 2011

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Dry age-related macular degeneration (AMD), an as-yet untreatable eye disease that causes blindness in older adults, made headlines last year when Massachusetts-based biotech Advanced Cell Technology launched a human embryonic stem cell (hESC) trial for the disease, marking only the third hESC trial approved by the US Food and Drug Administration. Now, two new trials are set to get underway—one also using hESCs and another that is turning to induced pluripotent stem cells (iPSCs), derived from adult skin cells. In addition to the hope the trials provide to the 10 or 15 percent of people older than 65 years affected by dry AMD, the parallel trials should allow scientists to compare the medical potential of the two stem cell types.

“The problem with [human] embryonic stem cells is that they’re so primitive that, when you induce them to differentiate, they can develop into teratomas, developmental tumors,” says Suzanne Ildstad, director of the Institute of Cellular Therapeutics at the University of Louisville in Kentucky who is not involved in the trials. “I don’t know if that’s known yet for iPS cells; I don’t think a lot of those questions are known yet.”

AMD is caused by damaged photoreceptors in the retina. The disease’s origin, however, is not the visual cells themselves; rather, a protective layer with the thickness of a single layer of cells, called the retinal pigment epithelium (RPE), ages and begins to disintegrate. This causes the overlying visual cells and underlying blood vessels susceptible to damage from the loss of nutrient regulation and dampened immune response in the retina.

The disease comes in two forms—the more severe, faster developing wet AMD, which recently made news as pharmaceutical companies argued over the best and cheapest drug to treat it, and the slower, progressive form, dry AMD. But although the dry form afflicts 90 percent of people with AMD, there currently is no treatment. “The only things that seem to be proven [to treat dry AMD]—and only mildly so—are dietary antioxidant supplements,” said Carl Sheridan, an ocular cell biologist at the University of Liverpool who is not involved in the trials. “Most of the treatments have been geared towards the wet form because it’s the severest form of the disease.”

But three stem cell trials, each of which target the dry form, are looking to change that. Dry AMD is prime territory for stem cell therapy because the best way to treat the disease is to completely replace the RPE—although this is no small feat. In the 1980s, researchers tried to inject replacement cells into the eye, but the treatment failed because replacing a few cells was not enough, explained Sheridan. “The membrane that they wanted the cells to attach to was also diseased, so short term success gave way to failure.”

To get around this problem, Masayo Takahashi, an opthamalogist at Japan’s RIKEN center, and her colleagues have developed RPE cells in culture from skin cells, first de-differentiating the cells into iPSCs and inducing differentiation into the retinal cell line. The researchers plan to coax the iPSC-derived RPE cells to form a thin cellular sheet that is injected under the retina to replace the entire RPE in one go. The researchers have done this successfully in more than 100 mice without tumor formation, and safety trials in AMD patients are expected to begin within three years.

Human embryonic stem cells.
Human embryonic stem cells.

Similarly, Advanced Cell Technology treated its first patients this past July, injecting RPE cells derived from hESCs under the retina as a “suspension of dissociated cells,” Robert Lanza, the chief scientific officer at Advanced Cell Technology, wrote to The Scientist in an email. And in a trial slated to begin next year, researchers at The London Project to Cure Blindness, led by stem cell biologist Pete Coffey, director of the Center for the Study of Macular Degeneration at the University of California, Santa Barbara, will inject hESC-derived RPE sheets behind patients’ retinas.

Beyond the potential to identify successful dry AMD treatments, these trials offer another opportunity to the field: the chance to judge whether iPSCs or hESCs make a more promising therapy for applications elsewhere. A challenge of hESCs is that they are generated from cells foreign to the patient and thus could be rejected by the body, requiring immunosuppressant drugs. iPSCs, on the other hand, are derived from the patient’s own skin, which should help avoid such immunorejection problems. But some researchers turn those skin cells into iPSCs using lentiviral vectors, which carry reprogramming factors to induce the stem cell-like state, and the virus could very well spur an immune reaction of its own, said Ildstad. Even though the RIKEN study doesn't use lentiviral vectors to bring the cell back to a pluripotent state, recent studies suggest that immune rejection may still be a risk.

“Rejection will always be an issue,” said Sheridan. “And we’re talking about an aged population that doesn’t take to immunosuppressants very well.”

However, the nature of the retina may limit how much these trials can teach researchers about stem cell medicine in general. “The eye is considered an immune-privileged site, which means the chances of the cells being rejected are considerably reduced,” Lanza said. Additionally, thanks to the nature of the RPE, the chances that the cells—either iPSCs or hESCs—will grow out of control or cause tumors may be considerably less in the retina than other parts of the body, said Takahashi, who has yet to see any signs of cancer in her mouse experiments.

Though the results remain out, some scientists are ready to put down their money. Due to his reservations about hESC rejection, for example, Sheridan is betting on the iPSC route. “Depending on how the iPS cells are generated, I would say the iPS cells have a better chance of success,” he said. Ildstad, however, preferred to hedge her bets and wait for more research. “There’s been a lot of promising data, but so far I don’t think there’s been a home run,” she said. “Clinical trials are the only way to decide whether they work or not.”

Correction: This story has been updated from its original version to correctly reflect that Advanced Cell Technology and The London Project to Cure Blindness’s hESC trials for dry AMD involves the injection of hESC-derived RPE cells, not hESCs. The Scientist regrets the error.

Clarification: This story has been updated from its original version to clarify that the RIKEN iPSC trial does not involve the use of lentiviral vectors to reprogram fibroblasts into RPE cells.

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Comments

Avatar of: feeed bottom

feeed bottom

Posts: 2

December 1, 2011

Hi Hannah,

  You have written that Advanced Cell Technology is " treated its first patients this past July, injecting hESCs under the retina as a “suspension of dissociated cells,â€쳌 Robert Lanza,"

First off Dr. Lanza & the FDA NEVER would have allowed "raw" human embryonic stem cells to be injected into a cohorts eye! LOL.  This would cause massive damage and teratoma's in the eye.  ACT through its IP takes hESC and makes them into RPE cells which are identical to native RPE cells.

iPSC show GREAT promise, however they are inheritantly dangerous in that the inducement part of the process is done by "virus" to induce to specific cell types. They have NOT been able to control the switch which controlls the off switch.  

You have also left out the ACT received EU approval for hESC to conduct macular degeneration trial using its exact same hRPE MA09 lines in its FDA trials.  Calling into question ACT's safety issue and ommiting that ACT has an assay test to sniff out rogue cells in a 1-20million detection process should have been mentioned.

ACT's animal models performed at Casey Eye institute were nothing short of a home run.  ZERO animals both RCS and Mouse cohorts (322 such animals) experience any teratoma's.

Closing, if a magazine online is going to call itself www.SCIENTIST.com I would recommend lifting the bar for ACTUAL science backed articles and not this version of cutting and pasting.

Superfeeed
www.investorstemcell.com

 

Avatar of: Masayo Takahashi

Masayo Takahashi

Posts: 1457

December 1, 2011

This is Masayo Takahashi. Thank you for including our project in the news.
We are carefully preparing for the wet-type AMD treatment.
Recently there are many ways to make iPS cells. Our iPS cells are generated without any viral vectors, so that they will not cause any immune response, I believe....(and we have evidences for that)

Avatar of:

Posts: 0

December 1, 2011

Hi Hannah,

  You have written that Advanced Cell Technology is " treated its first patients this past July, injecting hESCs under the retina as a “suspension of dissociated cells,â€쳌 Robert Lanza,"

First off Dr. Lanza & the FDA NEVER would have allowed "raw" human embryonic stem cells to be injected into a cohorts eye! LOL.  This would cause massive damage and teratoma's in the eye.  ACT through its IP takes hESC and makes them into RPE cells which are identical to native RPE cells.

iPSC show GREAT promise, however they are inheritantly dangerous in that the inducement part of the process is done by "virus" to induce to specific cell types. They have NOT been able to control the switch which controlls the off switch.  

You have also left out the ACT received EU approval for hESC to conduct macular degeneration trial using its exact same hRPE MA09 lines in its FDA trials.  Calling into question ACT's safety issue and ommiting that ACT has an assay test to sniff out rogue cells in a 1-20million detection process should have been mentioned.

ACT's animal models performed at Casey Eye institute were nothing short of a home run.  ZERO animals both RCS and Mouse cohorts (322 such animals) experience any teratoma's.

Closing, if a magazine online is going to call itself www.SCIENTIST.com I would recommend lifting the bar for ACTUAL science backed articles and not this version of cutting and pasting.

Superfeeed
www.investorstemcell.com

 

Avatar of:

Posts: 0

December 1, 2011

This is Masayo Takahashi. Thank you for including our project in the news.
We are carefully preparing for the wet-type AMD treatment.
Recently there are many ways to make iPS cells. Our iPS cells are generated without any viral vectors, so that they will not cause any immune response, I believe....(and we have evidences for that)

Avatar of:

Posts: 0

December 1, 2011

Hi Hannah,

  You have written that Advanced Cell Technology is " treated its first patients this past July, injecting hESCs under the retina as a “suspension of dissociated cells,â€쳌 Robert Lanza,"

First off Dr. Lanza & the FDA NEVER would have allowed "raw" human embryonic stem cells to be injected into a cohorts eye! LOL.  This would cause massive damage and teratoma's in the eye.  ACT through its IP takes hESC and makes them into RPE cells which are identical to native RPE cells.

iPSC show GREAT promise, however they are inheritantly dangerous in that the inducement part of the process is done by "virus" to induce to specific cell types. They have NOT been able to control the switch which controlls the off switch.  

You have also left out the ACT received EU approval for hESC to conduct macular degeneration trial using its exact same hRPE MA09 lines in its FDA trials.  Calling into question ACT's safety issue and ommiting that ACT has an assay test to sniff out rogue cells in a 1-20million detection process should have been mentioned.

ACT's animal models performed at Casey Eye institute were nothing short of a home run.  ZERO animals both RCS and Mouse cohorts (322 such animals) experience any teratoma's.

Closing, if a magazine online is going to call itself www.SCIENTIST.com I would recommend lifting the bar for ACTUAL science backed articles and not this version of cutting and pasting.

Superfeeed
www.investorstemcell.com

 

Avatar of:

Posts: 0

December 1, 2011

This is Masayo Takahashi. Thank you for including our project in the news.
We are carefully preparing for the wet-type AMD treatment.
Recently there are many ways to make iPS cells. Our iPS cells are generated without any viral vectors, so that they will not cause any immune response, I believe....(and we have evidences for that)

Avatar of:

Posts: 0

December 2, 2011

Hi Masayo!  We wrote a paper together several years ago about intraocular transplatation of the E1A-NR.3 cells.  I just wanted to congratulate you on your work and wish you all the best.

Avatar of:

Posts: 0

December 2, 2011

Hi, of course I remember you. Thank you for your message.

Avatar of:

Posts: 0

December 2, 2011

Masayo,

Are you using Protiens to induce instead of virus'?  What is your assay able to detect for rogue for your confidence level to be able to be so high? Do you have a Paper that can back up your statements? Thank you for clarifying that you are working on "WET" AMD, the author of this article had you working on "DRY".  Have you submitted your IND to the Japanese Ministry of Health & Welfare.?  How many cohorts? any information you can share would be GREAT

Thanks

sf

Avatar of:

Posts: 0

December 2, 2011

The article is a bit confusing: is the ipsc clinical trial protocol approved yet?

Avatar of:

Posts: 0

December 2, 2011

Hi Masayo!  We wrote a paper together several years ago about intraocular transplatation of the E1A-NR.3 cells.  I just wanted to congratulate you on your work and wish you all the best.

Avatar of:

Posts: 0

December 2, 2011

Hi, of course I remember you. Thank you for your message.

Avatar of:

Posts: 0

December 2, 2011

Masayo,

Are you using Protiens to induce instead of virus'?  What is your assay able to detect for rogue for your confidence level to be able to be so high? Do you have a Paper that can back up your statements? Thank you for clarifying that you are working on "WET" AMD, the author of this article had you working on "DRY".  Have you submitted your IND to the Japanese Ministry of Health & Welfare.?  How many cohorts? any information you can share would be GREAT

Thanks

sf

Avatar of:

Posts: 0

December 2, 2011

The article is a bit confusing: is the ipsc clinical trial protocol approved yet?

Avatar of: Gail

Gail

Posts: 1457

December 2, 2011

Hi Masayo!  We wrote a paper together several years ago about intraocular transplatation of the E1A-NR.3 cells.  I just wanted to congratulate you on your work and wish you all the best.

Avatar of: Masayo Takahashi

Masayo Takahashi

Posts: 1457

December 2, 2011

Hi, of course I remember you. Thank you for your message.

Avatar of: feeed bottom

feeed bottom

Posts: 2

December 2, 2011

Masayo,

Are you using Protiens to induce instead of virus'?  What is your assay able to detect for rogue for your confidence level to be able to be so high? Do you have a Paper that can back up your statements? Thank you for clarifying that you are working on "WET" AMD, the author of this article had you working on "DRY".  Have you submitted your IND to the Japanese Ministry of Health & Welfare.?  How many cohorts? any information you can share would be GREAT

Thanks

sf

Avatar of: PA M

PA M

Posts: 1457

December 2, 2011

The article is a bit confusing: is the ipsc clinical trial protocol approved yet?

Avatar of: Hannah Waters

Hannah Waters

Posts: 10

December 4, 2011

Hi,

The trial protocol is not yet approved. In Japan, researchers can test treatments in hospitals before approval, and use information from those preliminary treatments to work out the details for larger clinical trials. In our interview, Takahashi told me that she plans to do this. So there are still several steps to come, but she plans on beginning trials within 3 years.

Hannah

Avatar of: cramani

cramani

Posts: 1

December 4, 2011

Respected Masayo Takahashi
A great leap in retinal science
I am a veterinary ophthalmologist associated with projects on diabetic retinopathy in mice.

Avatar of:

Posts: 0

December 4, 2011

Hi,

The trial protocol is not yet approved. In Japan, researchers can test treatments in hospitals before approval, and use information from those preliminary treatments to work out the details for larger clinical trials. In our interview, Takahashi told me that she plans to do this. So there are still several steps to come, but she plans on beginning trials within 3 years.

Hannah

Avatar of:

Posts: 0

December 4, 2011

Respected Masayo Takahashi
A great leap in retinal science
I am a veterinary ophthalmologist associated with projects on diabetic retinopathy in mice.

Avatar of:

Posts: 0

December 4, 2011

Hi,

The trial protocol is not yet approved. In Japan, researchers can test treatments in hospitals before approval, and use information from those preliminary treatments to work out the details for larger clinical trials. In our interview, Takahashi told me that she plans to do this. So there are still several steps to come, but she plans on beginning trials within 3 years.

Hannah

Avatar of:

Posts: 0

December 4, 2011

Respected Masayo Takahashi
A great leap in retinal science
I am a veterinary ophthalmologist associated with projects on diabetic retinopathy in mice.

Avatar of:

Posts: 0

December 5, 2011

Very nice better in future I hope.
http://www.onlinebrandsshop.co...

Avatar of:

Posts: 0

December 5, 2011

Very nice better in future I hope.
http://www.onlinebrandsshop.co...

Avatar of: Angela  Gao

Angela Gao

Posts: 1457

December 5, 2011

Very nice better in future I hope.
http://www.onlinebrandsshop.co...

Avatar of: Lee Buckler

Lee Buckler

Posts: 2

December 9, 2011

Masayo.  Exciting work!  Can you please clarify for us as to whether your first use in humans will be an investigator-based trial under the Rinsho Kenkyu regulatory pathway or a formal IND under the Chicken pathway? And what is your expected time-frame to be launching your first human testing?

Avatar of: Lee Buckler

Lee Buckler

Posts: 2

December 9, 2011

Hannah is it your understanding then that hospital-based human testing is about to begin imminently?

Avatar of:

Posts: 0

December 9, 2011

Masayo.  Exciting work!  Can you please clarify for us as to whether your first use in humans will be an investigator-based trial under the Rinsho Kenkyu regulatory pathway or a formal IND under the Chicken pathway? And what is your expected time-frame to be launching your first human testing?

Avatar of:

Posts: 0

December 9, 2011

Hannah is it your understanding then that hospital-based human testing is about to begin imminently?

Avatar of:

Posts: 0

December 9, 2011

Masayo.  Exciting work!  Can you please clarify for us as to whether your first use in humans will be an investigator-based trial under the Rinsho Kenkyu regulatory pathway or a formal IND under the Chicken pathway? And what is your expected time-frame to be launching your first human testing?

Avatar of:

Posts: 0

December 9, 2011

Hannah is it your understanding then that hospital-based human testing is about to begin imminently?

Avatar of:

Posts: 0

December 15, 2011

Hi Lee,

Human testing is not imminent for the iPS trial. Still some animal safety tests to finish up, some protocols to optimize. They will begin within three years.

Thanks for your interest
Hannah

Avatar of:

Posts: 0

December 15, 2011

Hi Lee,

Human testing is not imminent for the iPS trial. Still some animal safety tests to finish up, some protocols to optimize. They will begin within three years.

Thanks for your interest
Hannah

Avatar of: Hannah Waters

Hannah Waters

Posts: 10

December 15, 2011

Hi Lee,

Human testing is not imminent for the iPS trial. Still some animal safety tests to finish up, some protocols to optimize. They will begin within three years.

Thanks for your interest
Hannah

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