Stem Cells in Ophthalmology Update 26 First Wet AMD Patient Treated With RPE Derived from iPS Cells

Earlier this week, it was reported that Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe had appeared in front of a 19-member health-ministry committee for the safety of the clinical use of stem cells. She was flanked by Shinya Yamanaka, the biologist who first created iPS cells. Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine for his breakthrough and now heads the Center for iPS Cell Research and Application in Kyoto. Takahashi was seeking approval to implant a retinal pigmented epithelial (RPE) sheet made from induced pluripotent stem (iPS) cells into a human patient.

Takahashi and her collaborators had shown in monkey and mice studies that iPS cells generated from the recipients' own cells did not provoke an immune reaction that causes them to be rejected. There had been concerns that iPS cells could cause tumours, but Takahashi's team found that to be unlikely in mice and monkeys.

To counter further fears that the process of producing iPS cells could cause dangerous mutations, Takahashi's team had performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants. The health ministry said that no problems were found and that the human trial could commence.

Only four days later (Friday, September 12th), the first patient was treated with the implanted sheet of RPE cells. She derived them from the patient's skin cells, after producing induced pluripotent stem (iPS) cells and then getting them to differentiate into retinal cells.

This is a major first for the stem cell and regenerative medicine fields.

Takahashi and her collaborators have been using induced pluripotent stem (iPS) cells to prepare a treatment for age-related macular degeneration. Unlike RPE derived from embryonic stem cells (i.e., as being done by Advanced Cell Technology), iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. The CDB trial will be the first opportunity for the technology to prove its clinical value.

A Japanese woman in her 70s is the world's first recipient of cells derived from induced pluripotent stem cells, a technology that has created great expectations since it could offer the same advantages as embryo-derived cells but without some of the controversial aspects and safety concerns.

In a two-hour procedure starting at 14:20 local time, a team of three eye specialists lead by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells into an eye of the Hyogo prefecture resident, who suffers from age-related macular degeneration.

The procedure took place at the Institute of Biomedical Research and Innovation Hospital, next to the RIKEN Center for Developmental Biology (CDB) where ophthalmologist Masayo Takahashi had developed and tested the epithelium sheets.

Afterwards, the patient experienced no effusive bleeding or other serious problems, as reported by RIKEN.

Another important element to this story is that Japan has a clinical translation pipeline that is now faster with recent changes in regulations than that of the US. For example, this and future iPS cell-based transplants were approved as part of a clinical study, a type of clinical research mechanism that doesn't exist in the US. It is safe to say that the same technology with the same research team and outstanding level of funding would still be at least a few years away from their first patient in the US due to the different regulatory scheme.

As noted by Dr. Paul Knoepfler, in his writeup about the procedure:

 “The patient is clearly a brave hero. The team transplanted a huge (from a bioengineering perspective) 1.3 x 3.0 mm sheet of RPEs into the retina of the patient, who did not have any clear immediate side effects from the procedure. Keep in mind again that this sheet was made indirectly from the patients own skin cells so it is an autologous (or self) transplant, a notion that 10 years ago would have seemed entirely like sci-fi.”

“This is not only a huge milestone, but also an astonishingly fast translation of iPS cell technology from the bench to the bedside.”

 “Also, on the positive side we have the encouraging results from the ongoing clinical trials from Advanced Cell Technology (ACT) using a similar approach to macular degeneration, but employing human embryonic stem cells to make the RPEs.”

“For the vision impaired and the broader stem cell field, it is heartening to have two such capable teams working to cure blindness with pluripotent stem cells.”

Sources:

1.Next-generation stem cells cleared for human trial: Japanese team will use 'iPS' cells to treat patient with degenerative eye disease, Nature, David Cyranoski, September 10, 2014.

2. Japanese woman is first recipient of next-generation stem cells: Surgeons implanted retinal tissue created after reverting the patient's own cells to 'pluripotent' state, Nature, David Cyranoski, September 12, 2014.

3. Stem cell landmark: patient receives first ever iPS cell-based transplant, Knoepfler Lab Stem Cell Blog, Paul Knoepfler, Septermber 12, 2014.

AMD Update 13 Retinal Procedures on the Rise

A new study, just published in the October issue of Archives of Ophthalmology and reported by Ophthalmology Web, MedPage Today, and Medscape Medical News,  shows that among those in the Medicare population (age 65 plus), treatments for retinal conditions nearly doubled between 1997 and 2007 – and this trend is expected to continue with the aging of the population and seniors living longer.

Since more than 50% of all permanent blindness in older Americans is the result of two different retinal diseases: age-related macular degeneration and diabetic retinopathy. Advancing age raises the risk for both conditions. As the number of US residents older than 65 years continues to grow -- the figure is predicted to double by 2040 -- the incidence of both diseases will likely escalate. To prepare for that prospect, the researchers analyzed Medicare fee-for-service claims filed during the 10-year period 1997 - 2007.

The new report, "Use of retinal procedures in Medicare beneficiaries from 1997 to 2007", by Pradeep Y. Ramulu, M.D., M.H.S., Ph.D., of the Wilmer Eye Institute, Johns Hopkins University, Baltimore, and colleagues, states:  "Retinal disease is highly prevalent among older individuals, and both age-related macular degeneration (AMD) and diabetic retinopathy account for more than half the irreversible blindness in older Americans. The prevalence of both macular degeneration and diabetic retinopathy increases with age, and the number of Americans affected by these conditions is expected to increase substantially as the number of Americans older than 65 years doubles from 2010 to 2040." The authors continued, as background information to the article, "The last decade has seen substantial changes in the treatment options available for many retinal diseases, particularly in the treatment of neovascular AMD," a form of the disease involving abnormal blood vessel growth in the eye.

Procedure volumes changed most markedly for treatments directed toward neovascular AMD. New treatments for this condition include intravitreal therapy-injections of drugs administered directly into the eye-of antibodies that block the formation of new blood vessels. (Both Avastin and Lucentis.) Between 1997 and 2001, fewer than 5,000 such injections were performed each year. However, rates more than doubled each year through 2006, increasing between 2001 (when 4,215 of these procedures were performed) and 2007 (when injections totaled 812,413). “These treatments now represent a major component of the treatment of retinal disease”, the researchers observed.

Aside from the VEGF inhibitors, other pharmacologic agents used for intraocular injections have included steroids for macular edema and pegaptanib (Macugen) for macular degeneration.

Prior to the introduction of pharmacologic agents, including Avastin in 2005  and Lucentis in 2006, the sole treatment option to have demonstrated benefit for choroidal neovascularization was thermal laser treatment. Thermal laser treatments also fell by 83% between 1997 and 2007, from a high of 56,966 to 13,821. Then in 2000, photodynamic therapy became available.

Photodynamic therapy peaked in 2004 with 133,565 procedures and then decreased 83 percent to 22,675 procedures in 2007. Laser treatment of choroidal lesions (potentially cancerous eye tumors) and neovascular AMD also decreased 83 percent, from a peak of 82,089 in 1999 to 13,821 in 2007.

Vitrectomy-surgical removal of the gel inside the eye, used to treat retinal detachments – increased 72 percent, from 11,212 in 1997 to 19,923 in 2007. Scleral buckling, a treatment for the same condition involving placing a silicon buckle around the eye, can be performed with or without vitrectomy. Scleral buckling alone became less common during the study period (a 69 percent decrease, from 8,691 to 2,660).

The increasing use of retinal procedures means that greater attention should be paid to the financial implications, the authors observed. The annual price tag for ranibizumab (Lucentis) is about $24,000 for a single patient, and investigations are needed to determine if lower-cost options (Avastin) could provide equivalent improvements in vision and quality of life. For instance, a study currently underway – the CATT Study,  is comparing the less costly Avastin with Lucentis in a double-blinded four-arm study. (Initial results of this study are expected to be released early next year.)

"Observing use patterns adds value, because it demonstrates how disease is treated and can be used to identify possible discrepancies between the best evidence-based treatments for a condition (as defined by clinical trials and meta-analyses from the literature) and current practice patterns," the authors concluded. "In this report, we observed that intravitreal injections of pharmacologic agents have gained widespread acceptance for the treatment of neovascular AMD and that vitrectomy is being increasingly applied to a wide range of retinal conditions."

The researchers stated several limitations to their study: the focus on only Medicare claims prohibited the discovery of trends in those younger than 65 years and prevents generalization of findings to those with private insurance, and in addition, possible systematic errors in coding may have biased results.

The National Institutes of Health supported the study.

References:

Arch Ophthalmol. 2010;128:1335-1340

Ophthalmology Web

MedPage Today

Medscape Medical News