Menu 20 A List of Writeups on Stem Cells Used in Ophthalmology

I realized that I’ve put posted more than 20 articles on the subject of using stem cells in ophthalmology, and thought interested readers might like to see a compilation in one place, with links to the full writeups, so here it is.

Menu 21 is a similar list with all of my gene therapy in ophthalmology articles.

Stem Cells

A Primer on the Use of Stem Cells in Ophthalmology

The what, who, and why of stem cells in ophthalmology.

What stem cells are all about, who’s involved, and what diseases of the eye are being treated.

Stem Cells in Ophthalmology -- An Update: AstraZeneca Joins the Fray

AstraZeneca and University College London (UCL) have announced a research partnership, to develop medicines that use stem cells to repair damaged eyesight in people with diabetes.

Stem Cells in Ophthalmology Update 2: ACT Gets Go-ahead to Treat Stargardt’s

Advanced Cell Technology’s request to begin treating patients with Stargardt’s disease was approved by the FDA. This will be the second trial using human embryonic stem cells. The first being granted to Geron to treat spinal disease.

A multi-center trial will involve twelve patients. If the results are positive, ACT anticipates filing for an IND to treat age-related macular degeneration, as well as filing to begin clinical trials in Europe in the very near future.

Stem Cells in Ophthalmology Update 3: ACT Files IND to Treat Dry AMD

Furthering its lead in stem cell research in ophthalmology, Advanced Cell Technology Inc., announced today that it  had filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration, to initiate a Phase I/II multicenter study for the  treatment of dry Age-Related Macular Degeneration (dry AMD) using human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells.

Stem Cells in Ophthalmology Update 4: ACT Receives FDA Approval to Use hESCs to Treat Dry AMD

Advanced Cell Technology Inc., announced today that it  had received approval from the FDA to commence its clinical trial using retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) to treat the dry form of age-related macular degeneration. ACT is now permitted to initiate a Phase I/II multicenter clinical trial to treat patients with dry AMD, the most common form of macular degeneration in the world. There are currently no approved treatments available for this prevalent disease of an aging global population. Dry AMD, representing a substantial global market opportunity and afflicts between 10-15 million Americans, and a further 10 million Europeans.

Stem Cells in Ophthalmology Update 5: Gene Defects Common in Induced Stem Cells

As the senior editor, John Gever, of MedPage Today reported, following the publication of three studies about induced pluripotent stem cells in the March 3rd, issue of Nature, “The road to regenerative medicine based on induced pluripotent stem cells (iPSCs) may have developed a giant pothole, with new studies showing that the cells are prone to several types of genetic defects.”

Stem Cells in Ophthalmology Update 6: Stemedica Paper Accepted for Presentation at ARVO

A safety study on the use of  stem cells in the eye, in a clinical study underway at the Fyodorov Federal Institution of Eye Microsurgery in Moscow, to treat diabetic retinopathy and diabetic optical neuropathy with stem cells derived from bone marrow, has been accepted for presentation as a poster at the upcoming ARVO (2011) Annual Meeting in Fort Lauderdale at the beginning of May. An abstract is shown below.

Stem Cells in Ophthalmology Update 7: Research Studies with Induced Pluripotent Stem Cells Suggest Opposite Results

Two research studies were published this week, about the use of induced pluripotent stem cells (iPSCs) in treating retinal problems, but with opposing results.

Stem Cells in Ophthalmology Update 8: ...and So It Begins

Advanced Cell Technology announced today that it had enrolled the first patients in its two Phase I/II clinical trials, using retinal pigment epithelial (RPE) cells derived from embryonic stem cells (hESCs) for treating Stargardt’s Macular Dystropyy (SMD) and for the treatment of the dry form of age-related macular degeneration (Dry AMD). The first of twelve patients in each trial were enrolled at the Jules Stein Eye Institute at the University of California, Los Angeles (UCLA).

Stem Cells in Ophthalmology Update 9: First Patients Treated

As I reported back on June 16th, Advanced Cell Technology had enrolled the first two patients in its Phase I/II clinical trials using retinal pigment epithelial (RPE) cells derived from embryonic stem cells (hESCs) for treating Stargardt’s Macular Dystrophy (SMD) and for the treatment of the dry form of age-related macular degeneration (Dry AMD). The company announced today that these first patients had now successfully received their first dose of the stem cells.

Stem Cells in Ophthalmology Update 10: ACT Expands Trials for Embryonic Stem Cells for Stargardt’s to the UK

In a news announcement today, Advanced Cell Technology said it had received approval to expand its stem cell treatment for Stargardt’s Macular Dystrophy to Moorfield’s Hospital in the UK.

Stem Cells in Ophthalmology Update 11: Catheter Delivered Stem Cells to Treat Geographic Atrophy in Dry AMD

The story of Centecor (now Janssen)/J&J’s program to deliver stem cells to the macular in the hopes of treating geographic atrophy in dry AMD.

Stem Cells in Ophthalmology Update 12: Updated Table of Company Participants

This table is now out-date. See the offer for up-to-date tables at the end of this menu.

Stem Cells in Ophthalmology Update 13: Advanced Cell Technology Update

In the wake of the 60 Minutes expose of illegitimate stem cell activities, I thought I would bring you good news about a couple of  legitimate, government approved clinical trials using stem cells.

Stem Cells in Ophthalmology Update 14: Current Stem Cell Clinical Trials

Again, this table is also out-of-date – see the offer below for the latest tables.

Stem Cells in Ophthalmology Update 15: Wills Eye Joins ACT’s Clinical Trials for Dry AMD Using Embryonic Stem Cell-derived RPE

The announcement that Wills Eye had joined the clinical trials.

Stem Cells in Ophthalmology Update 17: Recent ACT Updates

The four press releases from ACT while I was on vacation.

Stem Cells in Ophthalmology Update 18: StemCells Inc. Demonstrates That its Human Neural Stem Cells Preserve Vision – Gets FDA Authorization to Initiate Clinical Trial for Dry AMD

On January 30, 2012, StemCells Inc. announced the publication of preclinical data demonstrating that its proprietary HuCNS-SCr cells (purified human neural stem cells) protect host photoreceptors and preserve vision in an animal model of retinal disease. The preclinical results are highly relevant to human disorders of vision loss, the most notable of which is dry age-related macular degeneration (AMD). The study is available online at and will be featured as the cover article in the February issue of the international peer-reviewed European Journal of Neuroscience.

Stem Cells in Ophthalmology Update 19: ACT Adds Bascom Palmer as Another Clinical Site for Dry AMD Trials

Advanced Cell Technology said that Bascom Palmer Eye Institute had received IRB approval to become the third U.S. clinical site for testing ACT’s human embryonic stem cell-derived retinal pigment epithelial cells in the treatment of dry age-related macular degeneration. Bascom Palmer, one of the country’s premier eye institutes, joins UCLA’s Jules Stein Eye Institute and the Wills Eye Institute as the third U.S. site participating in the clinical trials.

Stem Cells in Ophthalmology Update 20: ACT Adds Mass Eye & Ear as Fourth Clinical Site for Dry AMD Trials

Advanced Cell Technology announced that Mass Eye & Ear Infirmary had received IRB approval to become the fourth clinical site for ACT’s embryonic stem cell trials in treating the dry form of age-related macular degeneration.

Harvard’s Mass Eye & Ear joins UCLA’s/Jules Stein, Wills Eye Institute, and Bascom Palmer in the ongoing Phase I/II clinical trial using subretinal injections of embryonic stem cell-derived retinal pigment epithelial cells.

In addition, it is my understanding that Moorfields Eye Hospital in London is awaiting final approval of an IND application to also participate in ACT’s clinical trial for dry AMD, along with its current participation as part of the company’s Stargardt’s disease stem cell clinical trial.

Stem Cells in Ophthalmology Update 21: Clinical Trial Details

In attempting to determine how many patients have been treated with stem cells for eye disorders, I quickly found that no one was keeping track – at least no one that I could find.

So, I decided to try and get this data. I have now obtained partial data for three of the 9 clinical trials underway and present this information in my new table.

Again, to obtain the latest version of this table, please request it via email.

Stem Cells in Ophthalmology Update 22: A Stargardt’s Clinical Trial Patient’s Story – In Her Own Words

Maurie Hill, a young woman with Stargardt’s disease was accepted into Advanced Cell Technology’s embryonic stem cell clinical trial. She was the first person to receive 100K of RPE cells derived from human embryonic stem cells.

In this blog post she describes her experiences.

And, finally, the blog entry on how to obtain the current, up-to-date tables of both stem cell companies and clinical trials underway, and the same for gene therapy companies and trials.

Current Resources: The Use of Stem Cells and Gene Therapy in Ophthalmology

Because I have been updating this information almost on a daily basis, I’ve decided to no longer post the information on this Journal (Irv Arons’ Journal), as it is practically out-of-date almost as soon as I post it. Therefore, I will only offer my tables of information to those who are interested in receiving them, and request them via email. I usually put notices on the appropriate LinkedIn Forums and on my Twitter feed (see sidebar) when there is substantial new information to report.

Here is what is currently available:

Stem Cells

Stem Cell Companies (and Institutions) Active in Ophthalmology

A list of snineteen companies and institutions working with stem cells for ophthalmic applications. The table lists collaborators, the cell type being used, and the applications against which the cells will be applied.

Stem Cell Therapy in Ophthalmology by Applications

A list of six ophthalmic applications being tested in clinical trials. The table includes which companies/institutions are involved, the clinical trial status, and the clinical trial number for those which are currently active. (Eleven active clinical trials are listed, with live links.)

Stem Cell Therapy in Ophthalmology -- Ongoing Clinical Trials 

A list of the the six ophthalmic application and the eleven clinical trials showing the number of patients to be treated in each clinical trial and the number treated to date (that I am aware of).

Gene Therapy

Gene Therapy Companies/Institutions Active in Ophthalmology

The table lists more than twenty-five companies and institutions actively pursuing gene therapy solutions to ophthalmic diseases. The table shows the delivery viral platform, the gene type being used (where known), the application, and clinical status.

Gene Therapy in Ophthalmology by Application

This table, like the one for stem cells, lists the ophthalmic indication, the company/institutions involved, the clinical status, and the clinical trial number. (Fifteen active clinical trials are listed, with live links.)

Gene Therapy in Ophthalmology -- Ongoing Clinical Trial Details

Again, as with the stem cell clinical trial table, this table lists all of the active clinical trials, the number of patients to be treated and the number of patients treated to date.

Anyone interested in receiving a copy of any or all of the above tables, please contact me via email (see the link in the side bar) and let me know which ones, or all four, that you wish to obtain. The tables are in pdf format, and as mentioned, contain live links to all of the clinical trials listed.

Irv Arons

Gene Therapy in Ophthalmology Update 7 2012 the Year for Gene Therapy

While I have previously written about the progress being made in the use of stem cells in ophthalmology (see Stem Cell Update 13) and described the 9-10 clinical trials currently underway or about to start (see Stem Cell Update 14), recent events point to 2012 becoming a breakthrough year for the use of gene therapy to overcome genetic defects that cause several ophthalmic diseases.

In the accompanying table, I list the fourteen clinical trials that I know about in the use of gene therapy in treating ophthalmic disease. Half of the trials are aimed at treating Leber’s Congenital Amaurosis (LCA), while three are for treating the wet form of AMD; one is underway for treating Choroideremia; one for Stargardt’s Disease; and two are aimed at different forms of retinitis pigmentosa (Autosomal Recessive RP and Usher Syndrome 1b).

In addition, I show at least twenty four clinical trials in either the pre-clinical (animal study) mode, or a couple in the IND-preparation mode. That is close to forty clinical trials using gene therapy to treat ophthalmic diseases.

The treatment of Leber’s using gene therapy has been ongoing for at least three years and, as I will show in the next update (Gene Therapy Update 8), those trials are going quite well, with many of the patients showing improved vision.

Finally, as another indicator that gene therapy will play an important role in ophthalmology in this year, Ocular Surgery News is about to begin a special section, OSN Retina, to be part of it’s coverage of the ophthalmic scene. The January 25 issue of Ocular Surgery News will include OSN Retina - a leading destination that will provide retina specialists with more relevant information specific to their field.. The premiere issue will include a feature on how  “Retinal gene therapy may pave the way for attempts to reverse genetic disease: Advancements in retinal gene therapy have prompted a collaborative effort to attain FDA approval.”

For those of you who wish a better understanding of how gene therapy works, and until I write the Primer on the Use of Gene Therapy in Ophthalmology, which I have threatened to write for the past year and a half, you can gain an understanding by reading my first article about gene therapy, written back in November 2010, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD by Retrosense.

Here then is my latest version of Gene Therapy in Ophthalmology by Application:

A pdf file of the table is available by email request.

Stem Cells in Ophthalmology Update 13 Advanced Cell Technology Update

In the wake of the 60 Minutes expose of illegitimate stem cell activities, I thought I would bring you good news about a couple of  legitimate, government approved clinical trials using stem cells.

As part of the Biotech Showcase 2012 conference program, being held in San Francisco, ACT company chairman and CEO, Gary Rabin will present talks on his company’s progress as part of two panels at the Regenerative Medicine State of the Industry Briefing. In advance of his two talks, the company released a statement about the ongoing clinical trials, results and timing, on his From the Chairman company blog.

In his statement, reproduced below, Rabin commented on the progress of two of the three government approved clinical trials currently underway at UCLA’s Jules Stein Eye Institute on treating Stargardt’s Macular Dystrophy and the dry form of age-related macular degeneration (Dry AMD). (See Update 8 and Update 9 for additional information.) (The other clinical trial, also for treating Stargardt’s, is taking place in the UK at Moorfields Eye Hospital in London.[Update 10])

As I reported last July, in Update 9, the first two patients in each of the UCLA trials were treated on July 12th. Since these are safety studies, the investigators are carefully watching the first patients response to the treatment before treating other patients in the twelve patient trials.

Rabin stated, “As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.” (Emphasis added by editor.)

Rabin went on to say, “I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.”

As for publishing the results of the studies, he said that the company would take the appropriate approach of “publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months.”

So, this is good news for the cell stem treatment of retinal diseases.

I have also just learned about several other clinical studies now underway in this field and will discuss them in a followup report (Update 14) to be published either later today or early tomorrow.

Now, here is the complete statement from Mr. Rabin, as taken from his company’s website:

January 10, 2012

Clinical Trials, Results, and Timing

Greetings,

For many of us, the New Year is a time not just for looking forward but for reflecting on events, achievements and lessons learned over the past year. I anticipate an amazing year ahead for ACT, and at the same time I also cannot help but reflect with pride on how far the company has come with its clinical programs over the past year.

IND Filing and Clinical Trials

I will never forget the moment I learned that the company's Investigational New Drug Application (IND) for its human clinical trial for Stargardt's Macular Dystrophy (SMD) had been approved by the FDA. It was clear then that ACT truly was on the road to potentially making medical history. So much has happened in the interim that it is hard to believe that happened only a bit over one year ago, in late November, 2010!

Shortly after that, our IND for Dry Age Related Macular Degeneration (Dry AMD) was also approved. The brief time since then has been a whirlwind of activity in preparation for the clinical trials, and we were enormously pleased and proud to start them in July, at the first site, UCLA's Jules Stein Eye Institute (JSEI).

As you are no doubt aware, the trials at UCLA are being conducted by Dr. Steven Schwartz of JSEI and overseen by our chief scientific officer, Dr. Robert Lanza. Each patient has received an injection of 50,000 hESC-derived RPE cells in one eye. Both trials will involve twelve patients, and are designed to evaluate the safety and tolerability of the injected RPE cells. Based on the results of the first patient in each study, we are authorized by the Data and Safety Monitoring Board (DSMB) to move forward with the next two patients in the studies, each of whom will also be treated with 50,000 RPE cells.

Part of what makes research and development in the regenerative medicine sector so exciting is that it involves sailing into largely uncharted waters. ACT's two trials are the only ongoing human embryonic stem cell-based trials, period. We are quite literally creating a new area of medicine. This means there is tremendous pressure on us to "get it right." The responsibility to provide the first-ever validation for this enormously promising new sector rests entirely on our shoulders.

I hope, then, that our many fans and followers can understand why this process takes some time. All eyes are on us, both from the standpoint of support and scrutiny. Should our trials succeed, it could provide the validation that the regenerative medicine sector has been in need of for some time. This is why, in every stage, we are bending over backwards to make sure we cross all our t's and dot all our i's. As the saying goes, Rome wasn't built in a day. If we can successfully complete these trials and bring these therapies to market, though, the potential benefits would be manifold:

*  The potential to at least partially restore sight to millions of people suffering from Dry AMD, the most common cause of blindness for people over age 55.

*  Provide a much-needed validation to the entire regenerative medicine sector.

*  Provide an enormously useful base of scientific knowledge on which we and others can develop other treatments and cures.

*  Last but not least, reward our investors for their patience and support with a return on their investment as befits a company with the only approved treatment for Dry AMD, which has a potential market size of $25-30 Billion in the US and Europe alone, as well as for SMD.

For many years, I was an equity market investment manager. That is an industry where you can evaluate results on a daily basis. Just because you can do that, though, does not mean that you should. The best investors, by far, look at long-term investment opportunities. Running a biotech company is not the same. I am well aware that we have many shareholders who want to know why we don't just treat patients and release results as fast we can, and as fast as available. To do so would be beyond foolhardy for a company like ACT. If there is anything this industry has had some issues with, it is credibility in the mainstream healthcare world. We plan to change that. But to do that, it can't happen overnight. Patient selection, clinical site selection, the timing of patient treatment, and unexpected non-ocular conditions of patients found in health screenings are among the major factors that impact patient treatment. Another factor in the timing of treating these new patients is that we will have at our disposal a new kind of three-dimensional retinal imaging technique, which has not previously been available. Believe me, the timing of patient surgeries has nothing to do with safety, efficacy or availability of suitable patients.

I know that many investors want us to go as fast as possible in treating patients. But there is a tortoise/hare effect here that I simply won't discuss now. I know that it is hard to be patient, but we are making every decision for the best interest of the company in the long run. We don't get bonus points for finishing the trial a few months earlier as compared to making it a truly game-changing medical opportunity. I know that many of you don't know me from Adam, but I'm a very methodical person. Look who we recently added to the Board - one of the leading scientists in the world; one of the best entrepreneurs in the world (founder of Life Alert and eFax), and the CFO of a highly-regarded biotech company considered to have made excellent, value-preserving large bio/pharma partnering deals. We have this under control.

One ill-conceived decision could set the company on a downward path (ACT has been there). Highly prestigious peer-reviewed medical journals do substantial review and due diligence. Top-rated eye hospitals and surgeons are very process-oriented and sometimes bureaucratic. Pushing them harder to move faster doesn't earn you any credibility or success.

Nevertheless, I am delighted to inform you that we are currently scheduled to treat our first patient in the UK at the end of next week or early the following week, and that we will be treating four additional US patients beginning that same following week.

Publishing Data

The question that inevitably comes up asks when we are going to publish the initial data from the trials. We are eagerly anticipating doing so but we are not going to just post it in raw form. This trial has the potential to make medical history and we want to share the initial results with the world in a strategic way.

The only appropriate approach with data this significant is publishing it in the form of a paper in a prestigious, peer-reviewed medical journal. However, the peer-review process takes time. The process typically takes several months, so I am actually quite thrilled that we are now moving toward the final stages of completing it, less than six months after the first patients were treated. We are far enough along that at this point the additional waiting time will be measured only in weeks, not months. We are coordinating the scientific publication with a general mainstream media release strategy (see below). When the paper is published, rest assured that we plan to leverage it to make sure it is very broadly known, not only in medicine, but in the broader medical and scientific community, as well as the investment community.

We sincerely appreciate everyone's patience as we continue this process. We are keenly aware that our investors, fans and other followers are anxious to see the data.

Thank you for your patience and thank you, as always, for your interest and support.

Gary Rabin

Chairman and CEO

Advanced Cell Technology, Inc.

Gene Therapy in Ophthalmology Update 20 Oxford BioMedica Clinical Trials Resume

Back in June, Oxford BioMedica announced that it had voluntarily paused recruitment for its clinical trials for wet AMD  (RetinoStat Phase I), Stargardt’s Disease (StarGen Phase I/IIa) and Usher’s Syndrome (UshStat Phase I/IIa). The company had halted recruitment of the aforementioned studies, as a precautionary measure, while it investigated the detection of very low concentrations of a potential impurity in its clinical trial material derived from a third party raw material.

Oxford has since performed extensive characterization studies using its newly developed, state-of-the-art analytical methods to identify the impurity as highly fragmented DNA derived from fetal bovine serum (FBS), the most widely-used growth supplement for cell culture media.  In light of these findings, Oxford remains convinced of the safety, integrity and quality of its LentiVector platform products and no safety concerns relating to any of the ocular products have been identified in any pre-clinical and clinical data generated to date.

Today, the company announced that following the submission of a comprehensive data package to the FDA and the French regulatory agency, ANSM, it has received agreement from both agencies to resume recruitment into its ocular clinical trials using the existing clinical trial material. The company will continue to use highly sensitive, state-of-the-art analytical methods to ensure the quality and integrity of its lentiviral vector products and will work with FDA and ANSM to define the necessary specifications for future batches of clinical trial material.

Oxford is now working closely with the clinical trial centers to obtain the necessary ethics committee approvals in order to resume recruitment into the clinical studies.

(For a list of the clinical site centers in the U.S. and France involved in the three studies, please take a look at my Gene Therapy Ongoing Clinical Trial Table at http://tinyurl.com/GeneTherapyClncal)

John Dawson, Chief Executive Officer of Oxford BioMedica, said: "We value our relationships with the regulatory authorities and are pleased that, on the basis of our extensive technical investigations to demonstrate the integrity of our products, FDA and ANSM agree with our proposal to resume treating patients in our ocular trials as soon as possible.

"We place the highest importance on safety, and our analytical methods and quality assurance processes are continuously evolving to ensure that we remain at the forefront of gene therapy development and manufacture. I am confident that, with significant opportunities ahead such as the recently-announced AMSCI project win, Oxford BioMedica will continue to lead the way in delivering novel gene therapies to patients."

For your information, Oxford BioMedica has reported that 9 of the 18 patients to be treated in the wet AMD clinical trial had been treated; 12 of the 28 patients in the Stargardt’s trial; and 3 of 18 patients in the Usher Syndrome trial had been treated prior to the halt in recruitment in June.

Coincidently, Genzyme, who is also running a gene therapy clinical trial to treat the wet form of AMD, also announced a halt in recruitment for its trial in July. No reason for the stoppage has been given and all attempts to determine why the halt in recruitment occurred have been rebuffed. As of the last time I had obtained reliable information about the Genzyme trial, 6 of 34 patients to be treated had been treated.


Genzyme Update – October 25, 2013

After many attempts to determine why Genzyme halted its clinical trial recruitment, I have finally received the answer. Here is the statement received from a spokesperson from Genzyme:

“We enrolled 19 patients in this clinical trial, all of whom have been treated. The protocol stated that we would enroll "up to 34" patients, but that number accounted for the possibility of replacing patients who withdrew early from the trial. Since no patients withdrew from the trial, we did not need to recruit 34 patients in order to meet the target enrollment numbers. The protocol specified that we planned to enroll 12 patients in the dose escalation part of the trial, and 10 patients in the second part of the trial, for a total of 22 patients. We stopped enrollment at 19 (three short of this target) purely because our clinical material was coming to the end of its stability protocol. There were no safety or product quality issues. We continue to monitor the 19 patients who were treated in our trial.”

Thank you Genzyme for providing this update.

Stem Cells in Ophthalmology Update 23 Maurie Hills’ Story More Details About The Stargardt’s Clinical Trial Patient

Back in early August, I wrote about Maurie Hill, a Stargardt’s disease patient who is undergoing stem cell treatment as part of the Advanced Cell Technology clinical trial in which an injection of retinal pigment epithelial (RPE) cells derived from human embryonic stem cells, was injected into her retina in an attempt to stop the progression of her disease and, hopefully, restore some vision that she has lost.

That first posting, A Stargardt’s Clinical Trial Patient’s Story – In Her Own Words, told Maurie’s story, taken from the blog she is writing about her experiences in this clinical trial.

Last week, Ricki Lewis, the author of The Forever Fix: Gene Therapy and the Boy Who Saved It, an excellent book about the gene therapy trials ongoing at Children’s Hospital in Philadelphia to treat Lebers Congenital Amaurosis, wrote more about Maurie Hill and the clinical trial.

Back in early summer, when Maurie first contacted me about the possibility of her taking part in the ACT clinical trial, I introduced her to Ricki. I thought that Ricki might be interested in writing another regenerative medicine book, this time about the use of stem cells. Ricki was interested, and made contact with Maurie, and this story is the result of that introduction.   

Human Embryonic Stem Cells Finally Reach Clinical Trials: Maurie’s Story

By: Ricki Lewis, PhD

Posted: September 27, 2012

DNA Science Blog in PLOS One Blogs

On July 11, Wills Eye Institute ophthalmologist Carl Regillo delicately placed 100,000 cells beneath the retina of 52-year-old Maurie Hill’s left eye. She was rapidly losing her vision due to Stargardt disease, an inherited macular dystrophy similar to the much more common dry age-related macular degeneration (AMD).

Maurie’s disease was far along, the normally lush forests of photoreceptor cells in the central macula area severely depleted, especially the cones that provide color vision. Would the introduced cells nestle among the ragged remnants of her retinal pigment epithelium (RPE) and take over, restoring the strangled energy supply to her remaining photoreceptors? They should, for the cells placed in Maurie’s eye weren’t ordinary cells. They were derived from human embryonic stem cells (hESCs).

I’ve waited 15 years to see human embryonic stem cells, or their “daughter” cells, make their way through clinical trials. And thanks to Maurie’s sharing her story, I’m witnessing translational medicine.

On September 29, 1997, The Scientist published my first stem cell article, Embryonic Stem Cells Debut to Little Media Attention. Alas, the public was still too enamored with Dolly the cloned sheep to pay much attention to cells that could both spawn specialized cell types and “self-renew,” maintaining a perpetual stream of hard-to-derive cells that could be used to both observe embryonic development and replace abnormal adult tissue. Over the years, public interest seemed to surface only on slow news days. And still the media report that the cells can “turn into” every cell type in the body – ignoring the very quality that defines the cells: the capacity for self-renewal, making more of themselves as their daughters specialize.

Partly because deriving hESCs until just a few years ago required destroying early human embryos, research using less objectionable stem cells accelerated. And while so-called “adult” and induced pluripotent stem cells (iPSCs) don’t require embryos and match patients so that the immune system isn’t provoked, embryonic stem cells remain the “gold standard” for scrutinizing a disease’s beginnings as the ball-of-cells early embryo folds into layers, contorts, develops organs, and grows. For example, hESCs recently glimpsed how the drug thalidomide harms embryos. The second use of hESCs is to generate useful specialized cells, such as sensory neurons to restore hearing. It’s this second application – hESCs as a source of implants – that is the focus of clinical trials for Stargardt disease and dry AMD.

Using hESCs could be incredibly economical. Just one can yield many millions of cells, the characteristics of the cells coaxed by the cocktails that researchers choose. And embryos can be returned to the freezer, unharmed. The RPE cells in Maurie’s eye came from an hESC line derived in 2005 by Robert Lanza and colleagues at Worcester, Mass.-based Advanced Cell Technology, one of five cell lines called NED for “no embryo destroyed.”

NED cells come from a protocol similar to pre-implantation genetic diagnosis (PGD), in which one cell of an 8-celled embryo is sampled to screen for genetic disease, and if all is well, the remaining 7-celled embryo is implanted in a uterus. PGD has been around since 1989. The ability to pluck out a cell at this stage without damaging the whole is a characteristic of our branch of the animal kingdom called indeterminate cleavage, for those who recall Zoology 101.

For a time, the first clinical trial to use hESC-derived cells — oligodendrocytes to treat spinal cord injury – was sponsored by Menlo-Park, CA–based Geron Corp. That effort ended in November 2011, due to cost. But eye diseases are perhaps a better first choice, because the retina is naturally shielded from the immune system.

I never expected to befriend one of the first people to be in an hESC clinical trial. But this past June, an email friend, Irv Arons, connected Maurie and me. She and her older sister Cindi would soon be on their way back from the Wills Eye Institute in Philadelphia, where they were being evaluated for the clinical trial to treat Stargardt disease. They’d be at the Albany Amtrak station on their return to Vermont, near my home.

The sisters have become so adept at using their peripheral vision to see around the central abyss in their visual fields that I couldn’t, at first, tell that anything was wrong with them. They were as excited as if they’d just won the lottery.

“Twelve people are participating. When I saw something about the clinical trial a year ago I thought yeah, right. But things just lined up,” Maurie said. She works 12 hours a week blogging for Ai Squared, maker of ZoomText software, and has a young daughter, a husband, and an associate’s degree in electronics and engineering technology.

Cindi agreed. “I was thinking this will never happen. There were too many barriers, too many things had to fall into place.”

The visual loss of Stargardt is slow. “In 3rd grade I‘d read very fast, but by 5th, I knew I should be able to read faster,” Maurie recalled. She struggled, not realizing anything was wrong, and didn’t even have an eye exam until her physical for college. “The doctor saw something and he sent me to an eye specialist who sent me to another eye specialist, but still I had no diagnosis.”

   

Eyechart: This is what Maurie Hill sees with her right eye covered when observing the eye chart from a meter away. (credit: Derek Bove)

At age 30, Maurie needed a physical for work, and again made the rounds of referrals. “I could still see pretty well, but some things bothered me: night driving and the lights coming at me and then disappearing, and being unable to recognize faces. I’d have trouble going from light to dark and vice versa.” By age 35, yet another job required a physical, and she went again to retinal specialists, but by this time she’d lost enough visual function to meet the diagnostic criteria for Stargardt. With every month, she could see less.

Meanwhile, Cindi’s vision was going downhill. “I went to my doctor, and I said ‘my sister has this, do I have it too?’ He ran out to open his textbook to see what it was, and said ‘yes, I think you have it,” Cindi said. She taught special ed for 14 years before she had to leave, no longer able to do the visual tasks required for her job, even with the adaptive technology that had helped for a decade.

The sisters have four other siblings. True to Mendel’s first law for single-gene inheritance, their older brother has Stargardt too, although his case is so mild that until recently he could read normal-sized print, although slowly and with great eyestrain.

In 2009, the siblings heard about successful gene therapy for Leber congenital amaurosisamaurosis  another inherited retinal disease. Could they have gene therapy too?

In May 2009, the family went to the National Eye Institute to confirm Maurie’s 1995 diagnosis, which had been based on clinical findings. But genetic test results indicated that the family didn’t have a mutation in the ABCA4 gene, as 40% of those diagnosed with Stargardt do, or any other mutation. “That was a little disappointing, since we knew the mutation would have to be known to do gene therapy,” recalled Maurie.

But what about stem cell therapy?

Maurie read (by zooming her text and using her peripheral vision) a news release from Advanced Cell Technology announcing that their researchers had derived RPE cells from hESCs. The first two applications would be dry age-related macular degeneration and Stargardt disease. Mice and rats had responded well.

So Maurie called her siblings, and her brother called ACT immediately, but got nowhere. The timing just wasn’t right.

By late 2010, FDA had approved ACTs testing the RPE cells for safety, and clinicaltrials.gov officially announced the upcoming experiments in late April 2011. Four cohorts of three Stargardt patients each would receive escalating doses, starting with 50,000 RPE cells. The AMD trial would proceed in parallel.

Results came very quickly, published online in January 2012’s Lancet. And the news was good. The cells hadn’t harmed the first two patients, a woman in her 70s with AMD and a 51-year-old woman with Stargardt, both treated at the Jules Stein Eye Institute in Los Angeles.

A fear of using embryonic stem cells is that they can give rise to teratomas, which are bizarre tumors festooned with bits of specialized tissue such as teeth and hair. If an ES cell lurked among the RPE cells put into a patient’s eye, a teratoma might sprout. But since this hadn’t happened by three months, and neither woman had inflammation or immune rejection, the therapy passed the first safety hurdle. (A year out, the 9 patients treated so far report more vibrant color vision and improved visual acuity. The first woman treated, for example, could detect only hand-waving before the procedure, but can now read three lines on an eye chart.)

After the sisters heard the two LA patients on NPR January 23, Maurie called the clinical trial director at the nearest participating center, the Wills Eye Institute. When she finally got through, she learned that the center would consider only local patients, so they’d be easier to follow. But a month later, her local eye doctor urged her not to give up.

So Maurie called back, and finally the timing was right. “The research coordinator answered and was flowing with information.” Elated, Maurie sent her medical records right away – she had fortuitously just had a colonoscopy (cancer is grounds for exclusion due to the teratomas), mammogram, Pap smear, cholesterol test, and more.

Dr. Regillo liked Maurie’s test results. She was the ideal clinical trial participant – healthy except for the condition under study, a rarity. When Maurie got the good news, she asked if she could bring Cindi along. Both sisters agreed to foot the Amtrak bills. They told me about the visit when I met them in the Albany train station. Maurie was in; Cindi is still being evaluated.

The big day came in just a month. On July 11, Maurie and Cindi arrived a little before noon, surprised at the video cameras. Every step of the procedure had been meticulously choreographed and practiced, with trial runs to identify the time with the lightest traffic on a midsummer Wednesday between New Jersey, where the precious cells were on ice, and Philadelphia.

The cells arrived in a red cooler, the clock ticking down the 3 hours they could survive. Testing for viability and contamination took 30 minutes, and then the procedure itself took just 3 minutes.

Maurie hadn’t expected to be awake and aware as the descendants of human embryonic stem cells flooded her eye, although she’d chosen local anesthesia. “I actually saw the needle come in the inside of my eye! Dr. Rigello said, ‘Can you see that?” I said I clearly saw the needle coming in from the left, and he said, ‘Yup!’ I could see the fluid coming out and forming a little puddle. It was the coolest thing. And everyone was so excited that I saw it!”

Maurie Hill, shortly after having 100,000 retinal pigment epithelium (RPE) cells derived from human embryonic stem cells (hESCs) placed in her left eye

And so Maurie Hill joins the brave and selfless individuals who have volunteered to participate in clinical trials, who make new treatments possible for many. But Maurie’s going one huge step farther: she’s blogging about her progress.

To be continued …

The Author

Ricki Lewis is a science writer with a PhD in genetics. The author of several textbooks and thousands of articles in scientific, medical, and consumer publications, Ricki's first narrative nonfiction book, "The Forever Fix: Gene Therapy and the Boy Who Saved It," was published by St. Martin's Press in March 2012. In addition to writing, Ricki provides genetic counseling for parents-to-be at CareNet Medical Group in Schenectady, NY and teaches "Genethics" an online course for master's degree students at the Alden March Bioethics Institute of Albany Medical Center.