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

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

From afar (my home), I reviewed the program for the Retina SubSpecialty Program and decided to write about several of the presentations on the program. I was able to obtain a copy of the program abstracts (from a friend in attendance) and got in touch with each of the presenters of interest and requested an electronic copy of their presentations. The presentations of interest included the following:

The Genetics of Retinitis Pigmentosa by Stephen Tsang, MD;
Attacking Leber Congenital Amaurosi by Albert Maguire, MD;
Gene Testing and AMD: Are We Ready to Start? by Ivana Kim, MD;
Dry AMD Treatment: How Will We Define Sucess? by Phil Rosenfeld, MD;
Drug Delivery Implants for Geographic Atrophy by Baruch Kupperman, MD;
A Complement-Based Gene Therapy for AMD by Elias Reichel, MD; and,
The Promise of Stem Cells for AMD and Retinal Degenerations by Marco Zarbin, PhD.

In addition, in following the reporting by various sources of the meeting, I discovered that a paper by Dr. Michael Samuel about the delivery of stem cells to the macula via a specialized catheter was also presented (apparently in an update session). I was not familiar with either this approach or the program (even after writing A Primer on the Use of Stem Cells in Ophthalmology in September, last year), so I got in touch with Dr. Samuel (and his sponsor, iScience Interventional, the supplier of the special delivery catheter) and asked their permission to obtain an electronic copy of the presentation. After some back and forth, I learned that the actual sponsor of the clinical study that Dr. Samuel was reporting on, was the Centecor Division of Johnson & Johnson, from whom I would also need permission.

I attempted to get in touch with the appropriate people at Centecor/J&J and am still waiting to hear back from them.

In the meantime, after a little due diligence online, I discovered a couple of things. First, J&J’s Centecor was the sponsor of two ophthalmic clinical trials using its CNTO2476 stem cells, one for the treatment of retinitis pigmentosa (now terminated for business reasons – but no further explanation given) and the second for treating geographic atrophy in dry AMD.

I also came across a review article by Dr. Allen Ho on the GA program in the current (October) issue of Retina Today. Finally, I also discovered that EyeTube.net had a video online of Dr. Samuel presenting the results of the initial GA trial on the first set of twelve patients, apparently summarizing his presentation from the Retina SubSpecialty Day session.

So, armed with all of this new found information, I believe I can now tell the story of Centecor/J&J’s program to deliver stem cells to the macular in the hopes of treating geographic atrophy.

The other stories selected from the Retina SubSpecialty Day Program will be presented in other entries on this blog.

Novel Technique for Stem Cell Therapy to the Subretinal Space
Dr. Michael Samuel, and

Human Adult Umbilical Stem Cells: Potential Treatment for Atrophic AMD
Dr. Allen Ho


The Program

Treating Geographic Atrophy

As described by Dr. Ho, “Geographic atrophy (GA) is a slowly progressive pathology in nonexudative ("dry") age-related macular degeneration (AMD), for which there is currently no safe and effective treatment. Investigational strategies for treatment of atrophic AMD include oral nutraceutical formulations, vitamin A visual cycle modulators, and injectable molecular interventions with molecular targets such as complement system modulators to retard the progression of GA. The goals of these investigational interventions include preventing photoreceptor and retinal pigment epithelial (RPE) cell loss, reducing the load of toxic metabolites in these cells, and suppressing or modulating inflammation.

Another approach under investigation in relation to preventing photoreceptor and RPE cell loss in GA is cell-based therapy – the harvesting and transfer of stem cells to support or replace diseased cells. Traditional pharmaceutical agents work on a molecular level; cell-based therapies work on a cellular level to restore or preserve cellular function.

The main sources for the cells used in cell-based therapies include embryonic stem cells, which have been controversial, and adult stem cells. Sources for adult stem cells include bone, blood, umbilical cord, and, in the eye, the corneal limbus.”

The Approach

Again, as Dr. Ho has written, “Two approaches are used in stem-cell therapies: regenerative and trophic (Figure 1). In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. That is, they are progressed to become another cell type: for example, corneal stem cells (or retinal pigment epithelial [RPE] cells). These functional cells are intended to replace lost or injured native cells to restore organ function. In the trophic approach, the stem cells are themselves the product. The adult cells are isolated, characterized, and expanded, but they remain differentiated, not progressed to become another cell type. In this approach, the role of the cells is to support or repair injured native tissue and preserve function by altering the microenvironment of the injured tissue, for example through cytokines or cell-to-cell interactions.

Figure 1. Regenerative (A) and trophic (B) stem-cell therapy. In the regenerative approach, embryonic or adult stem cells are isolated, expanded (grown to larger number of cells), and differentiated into the stem-cell therapy product. In the trophic approach, the stem cells are themselves the product.

In the regenerative approach, the stem cells are the precursor to the product. An example of regenerative stem-cell-based therapy is corneal limbal stem cell transplantation, in which autologous allogeneic adult corneal limbal stem cells from the palisades of Vogt are transplanted to help the corneal epithelium regenerate. The corneal limbal stem cells are transplanted onto the surface of the eye, repopulating the damaged cornea.

One example of trophic cell-based therapy is the NT-501 (Neurotech), an intraocular device that delivers ciliary neurotrophic factor (CNTF), a protein that has been investigated for the treatment of motor neuron disease, to the posterior segment. The implant contains human RPE cells that have been genetically modified to secrete CNTF. In a phase 2 clinical trial, NT-501 slowed the loss of vision in patients with GA due to dry AMD. Implanted in an OR-based procedure, the technology was superior to sham injection in stabilizing best corrected visual acuity (BCVA) at 12 months. No serious adverse events were reported, and the implant was well tolerated. Further study of this technology is ongoing.

Another example with a putative trophic mode of action is human adult umbilical stem cell rescue of photoreceptor cells. In the Royal College of Surgeons rat, in which most of the photoreceptors degrade before 100 days of age because of a defect in the RPE, both structure and function of the retina were preserved after transplantation of human umbilical-derived cells. Of 4 cell types evaluated, the umbilical-tissue derived cells demonstrated the best photoreceptor rescue.”

Editor’s Note: It must be noted that other companies besides Centecor/J&J are pursuing stem cells – and even gene therapy – approaches to treating the dry state of AMD. Advanced Cell Technology has an ongoing clinical study, using human embryonic stem cell derived RPE in treating dry AMD (as well as Stargardt’s disease). Retrosense – among others – using gene therapy, plans to study dry AMD after it gets its retinitis pigmentosa (RP) program underway, and Oxford BioMedica has just begun a clinical study to treat a form of RP associated with Usher’s Syndrome (type 1B) with gene therapy. (I have written about all three of these companies programs in this space.)

The Clinical Trial

As noted above, and also reported by Dr. Ho, Centecor/J&J has initiated a clinical study using their CNTO 2746 therapy in patients with geographic atrophy associated with the dry form of AMD. This clinical trial was initiated in October 2010. As stated in the clinical trial information sheet, the main purpose of the study is to assess the effects (good and bad) of the CNTO 2476  therapy for patients with age related macular degeneration. Patients will have CNTO 2476 injected by the surgeon into the subretinal space of the macula of one of their eyes. The patients will then be assessed over a period of at least one year by their surgeon.

CNTO 2476 is composed of human umbilical tissue-derived stem cells (hUTC) from Centocor, Inc.

Twelve patients were enrolled in the Phase I dose escalation and safety study at sites in Philadelphia and Los Angeles. In the Phase II study, an additional 56 patients will be enrolled at the two current and four additional study centers, and will be randomized to 1 of 2 optimal doses identified during Phase I.

Surgical Delivery

Again, as described by Dr. Ho, “CNTO 2476 is delivered to the subretinal space with the iTrack 275 microcatheter (iScience, Menlo Park, CA). The microcatheter is combined with a fiberoptic illuminator and a microcalibrated pump, which ensures rate-controlled delivery of the stem cell product.

The microcatheter is inserted through a sclerotomy and choroidal fistula. A wire-tipped cannula is used to inject sodium hyaluronate viscoelastic (Healon, Abbott Medical Optics) to create a peripheral retinal bleb; the retinal elevation allows subretinal cannulation of the probe. Ultrasound is used to visualize the creation of the bleb, and it can be directly visualized with an intraocular endoscope. The illuminated beacon tip of the microcatheter then can be visualized through the pupil to verify its position in the posterior pole, and CNTO 2476 is delivered to the subretinal space near the macular GA (Figure 2). The surgical procedure is challenging and continues to evolve.”

Figure 2. The iTrack is guided from the choroidotomy through the subretinal space to the macula.

Results to Date

(This is where I had hoped to report on Dr. Samuel’s presentation, given at the SubSpecialty session. But, since I have yet to receive it, I will relate what he said in his video on EyeTube, along with what has been reported by others who were at the meeting.)

From the OSNSupersite report:

Three serious adverse events were reported in a phase 1b study of 12 patients with advanced geographic atrophy undergoing a surgical technique that delivers mesenchymal stem cells via catheter to the macula.

"First and foremost, this was a safety study," Michael A. Samuel, MD, said, while delivering the "broad strokes" of the study's interim results at Retina Subspecialty Day preceding the annual meeting of the American Academy of Ophthalmology.

"The surgical procedure is difficult, and it's not something we're used to," he said, "...but we've learned many things, and we've refined the surgery."

The surgical technique employs a lighted catheter (iScience) that passes through a choroidotomy and delivers stem cells to the targeted area.

There was a clinical response in that half the patients in the study had "very substantial improvement in vision," he said.

Additional information derived from the EyeTube video:

The iTrack 275 catheter enabled delivery into the subretinal space below the macula.
In the last patient treated (at Wills Hospital in Philadelphia), visualization was done through an endoscope that enabled a much better look at where the catheter was delivering the stem cells and was considered a “quantum leap” forward in visualization.

Of the 12 patients treated, six had improved vision; four gained +4 lines, while 2 gained +6 lines. Of the remaining patients, 2 had retinal detachments and 1 lost vision because of macular pucker/loss of traction.

The Phase II study is expected to get underway in the next couple of months (see notes above in the Clinical Trial section).