Saturday, September 13, 2014

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.”


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


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