Public interest in stem cell research began in earnest in the late 1990s, not long after the cloning of Dolly the sheep and news reports that scientists had derived the first embryonic stem cell (ESC) line.¹ Lay media hype surrounding two other major milestones — the discovery in 2007 that induced pluripotent (‘adult’) stem cells could be ‘turned back’ to an ESC-like state² and the report in 2013 that patient-specific ESCs could be created by means of ‘therapeutic cloning’³ — served to further strengthen the public’s belief in the promise of stem cell research.

The fulfillment of that promise has, at times, seemed to be right around the corner, due in part to powerful human yearnings and the emergence of ever more sophisticated technology. However, as of May 2017, the only treatment involving stem cells that has received FDA approval is hematopoietic stem cell transplantation for patients with hematologic diseases. Stem cell treatments for retinal diseases, among many others, remain in the early experimental stages. This fact, until very recently, has been inadequately communicated to patients who seek treatment for retinal diseases.

In March 2017, The New York Times reported that three patients lost their eyesight after paying $5,000 each to receive stem cell treatments for macular degeneration from a poorly regulated clinic in Florida.⁴ This very public announcement about potential dangers associated with stem cell treatment came on the heels of a widely read peer-reviewed article on the topic published in the New England Journal of Medicine.⁵ The article provides a detailed overview of the patient stories described in the The New York Times and raises critical issues about stem cell treatment for retinal diseases. In an accompanying editorial also cited by The New York Times,⁶ scientists from the Food and Drug Administration warn that most current stem-cell therapy claims are based on little, if any, clinical evidence of safety or efficacy.

WHAT DO PATIENTS NEED TO KNOW?

The recent Times and NEJM articles suggest that most patients have little basic information about stem cells or stem cell clinics, and little if any ability to ascertain whether or not a particular treatment is based on sound preclinical and clinical science.

“There are roughly 500 stem cell clinics in the United States,” says Thomas Albini, MD, of the Bascom Palmer Eye Institute in Miami. Dr. Albini was interviewed for the Times article, and co-authored one of the recent NEJM articles. “They are located pretty broadly throughout the country, and offer treatment for a wide variety of diseases. From what we can gather from internet research, there are probably about two dozen or so clinics offering therapies for eye-related problems. These clinics frequently offer the same treatment for a wide variety of eye-related diagnoses, which is highly suspect, and unusual for genuinely effective treatments. They will treat everything from optic neuritis to macular degeneration to congenital retinal dystrophies with the same procedure.”

The use of a single stem cell procedure for the treatment of multiple eye-related conditions is just one of many red flags that patients should consider.

“Many stem cell clinics in the U.S. are operating without physician supervision,” notes Dr. Albini. “If a physician is involved, typically that individual is not an expert in treating patients with eye disease. Clinics that don’t have ophthalmologists on staff are clearly dangerous. There also are some ophthalmologists offering unproven therapies. It is important for patients to be counseled, so they understand the difference between an unproven therapy and a treatment that has real safety and efficacy data. So far, none of the stem cell treatments for eye disease have adequate safety and efficacy data or FDA approval, and all treatments are still in the early stages of research. Patients must understand that when they receive an unproven therapy, they really are taking a great risk. As we have seen, some of these procedures can have very serious consequences.”

Because legitimate experimental research typically is sponsored by government or corporate funding, a stem cell clinic that requests money for participation in research may be another red flag.

“When a patient participates in a clinical trial, typically everything is paid for,” says Dr. Albini. “So, if patients are asked to pay, they should think twice about the treatment — most likely the organization is just interested in their money. A practitioner willing to conduct experimental treatments on both eyes on the same occasion is another red flag. And patients should be counseled that there is no guarantee that a study indexed on ClinicalTrials.gov is legitimate. A study that appears on that site has not necessarily filed with FDA, and may not even be a real study at all.”

Ensuring patients are adequately informed about stem cell research may be an uphill battle because of the vast amount of literature produced by unscrupulous authors and publishers.

“There are numerous books about the so-called stem cell revolution,” says Dr. Albini. “Many of these are actually written by MDs, and they paint a picture of alternative therapies being unfairly disliked by the medical establishment. They explain to readers why the mainstream medical establishment is not interested in them, or why they are ostracized and unfairly judged. They offer excuses to explain why they have to operate outside the norm. Some books list macular degeneration and other eye diseases among the 30 or 40 diseases they claim can be treated with stem cells, based on absolutely no data. Unfortunately, many patients who feel they don’t have other options get this material and want to try the treatments.”

WHAT DO PHYSICIANS NEED TO KNOW?

The number of patients seeking treatment for injuries related to stem cell therapies is likely to increase. Yet little information exists regarding the best approach for the treatment of these injuries.

“The commonalities among the injured patients we’ve seen so far — including, but not limited to, those described in NEJM article — are a proliferation of membranes on the surface of the retina and delayed retinal detachment,” says Dr. Albini. “These are the most common injuries and they have resulted in a significant reduction of vision. The cases we published in the NEJM are the worst, but certainly other patients have lost a high degree of meaningful vision.

“A patient who calls with a stem-cell treatment-related injury should be seen immediately, although, unfortunately, we have had only very minimal success in restoring vision in these patients. Many patients complain of pain and pressure, so those complaints need to be addressed. The pain we’ve been able to treat, but there may not be anything that can be done to restore vision. It makes sense to operate and try to re-attach the retina. Certainly, the sooner we see the patient, the better off the patient will be, but the outcomes have been very limited.”

CURRENT STEM CELL RESEARCH: PLENTY OF PROMISE

A timely article recently published by the American Journal of Ophthalmology¹ provides a good overview of legitimate stem cell research for retina diseases, and offers clarifications that may be useful for retina surgeons, as well as information that may make it easier to guide treatment decision-making.

“While most retinal specialists understand what a stem cell is,” says lead author Rajesh C. Rao, MD, of the University of Michigan Kellogg Eye Center, “it is worth reviewing the different types to better evaluate clinical trials and advise patients regarding current research. When physicians are reviewing clinical trials, it’s important to note whether the term ‘stem cell’ is being rigorously defined. What kind of cell is being used in the trial? Is it a retinal stem cell, which self-renews and can make specialized retinal tissues? Is it an embryonic stem cell, which also can self-renew and make 200 or more different tissues? Is it an adipose (fat) progeni-tor cell, which can make more fat cells? It’s important to keep in mind that the term ‘stem cell’ has become a buzz word that often is used to attract unwitting patients, and often is used incorrectly.”

Experts still believe that stem cells have enormous poten-tial to treat diseases. However, at least in the retinal field, it is far too soon to point to successful patient outcomes.

“We are not yet at a point where we can say whether any experimental treatment is efficacious,” says Dr. Rao. “In the retina field, stem cell research begins with a fundamental truth: retinal cells don’t repair themselves when they are dysfunctional, and when they die, they do not regenerate. Currently, researchers are able to generate retinal cells from stem cells, and grow retinal cells in a dish. Are these cells, which currently are being made in a dish, mature cells? Are they the equivalent of the normal, light sensitive retinal cells of a human adult? No, not yet — that is still very much a work in progress.”

“However,” adds Dr. Rao, “we are now able to study human retinal cells that we were never able to access and study before in large numbers, thanks to stem cell technology. Researchers are now using stem cells to try to gain a better idea of how the retina is built. Eventually, when mechanisms underlying retinal development are better understood, novel drugs may be tested to see, first, whether key retinal cells, such as retinal pigment epithelium (RPE) or light-sensitive photoreceptor cells, can be regenerated without the injection of cells into the retina. Alternatively, millions of compounds in drug libraries may be tested to see whether a drug might allow retinal cells to develop more fully in a dish, or whether a drug might help regenerate retinal cells that die, for example, in macular degeneration. That is where the power of stem cells currently lies. Those are some of the general aims of current research.”

Despite exciting reports of progress in preclinical settings, occasionally there are new reports that cause experts to pause and improve procedures for testing stem cells.² Accordingly, progress continues to lag behind patient hopes and expectations.

There is no way to quickly determine which of the approximately 30 clinical trials involving stem cell research listed on ClinicalTrials.gov may be considered legitimate. Until physicians and scientists with knowledge of stem cell research and clinical trials are willing to provide the service of preparing a reputable list, patients will be dependent on their doctors for guidance.

“Physicians who wish to counsel patients but are not involved in this kind of research should reach out to talk with experts they know or trust,” says Dr. Rao. “And here is an important opportunity in the retina community. It might make sense for major societies, such as ASRS or others, to designate individuals they deem to be experts in stem cell research, who can be called on to provide guidance or general recommendations in evaluating these trials. Not with regard to the efficacy of a treatment, of course, but with regard to whether the trial even follows some of the basic rules or regulations that we expect of legitimate trials, and is based on a scientific premise. Experts in the stem cell field may be able to quickly apply a long checklist of important red flags.”

REFERENCES

1. Rao RC, Dedania VS, Johnson MW. Stem cells for retinal disease: a perspective on the promise and perils. Am J Ophthalmol. 2017;179:32-38.
2. Mandai M, Watanabe A, Kurimoto Y, et al. Autologous induced stem cell-derived retinal cells for macular degeneration. N Engl J Med. 017;376(11): 1038-1046.

A retina surgeon who encounters one of these patients should report the encounter immediately to the research and therapeutic surveillance committee at the American Society of Retinal Specialists. Such encounters will likely continue until FDA regulations that outlaw the practices of stem cell clinics are enforced.

“The FDA has clarified that they believe that these stem cell clinics don’t meet the criteria required of legitimate studies,” says Dr. Albini. “These clinics say that although they are not FDA regulated, they are FDA compliant, with regard to using minimally manipulated tissues (See Kuriyan et al.) However, it’s hard to see how the use of adipose-derived stem cells for eye-related diseases could possibly be in line with FDA regulations. The FDA has clarified that many of these stem cell clinics clearly do not meet the letter of the law, and that they do indeed need to file paperwork with the FDA. Investigators conducting legitimate stem cell research, of which there is quite a bit (See sidebar, page 6), seem to have no problem filing with the FDA.”

Patients mentioned in the Times article believed that they were participating in a legitimate study because they discovered it on ClinicalTrials.gov , and because they signed what seemed to be standard consent forms.

“However, their consent did not reflect that they were in a study,” says Dr. Albini. “When the protocol for this so-called study was withdrawn from ClinicalTrials.gov , we learned that no patients had been recruited for the study. Some U.S. stem cell clinics list themselves on Clinical trials.gov as an advertising ploy. ClinicalTrials.gov posts many studies and has a very low bar for what they put on their website. They don’t really have the manpower to audit all the postings and ensure that they are legitimate studies.”

Instead, ClinicalTrials.gov has begun to use a disclaimer to warn patients about some of the listings on their site.

“My understanding is that now, on the top of every page, there is a disclaimer to the effect that a listing alone does not in any way mean that a study has been approved by any government agency,” says Dr. Albini. “I also understand that the FDA has reopened their investigation into the cases mentioned in our article. It will be interesting to see whether there is enough political backing to support prosecution by the FDA. We can have guidelines and clarifications, but until these are tested in a court of law, we will never know where things stand. Most of these places are still conducting business, and, in fact, the clinic that treated the patients described in our article is still open for business; it is still treating a whole host of other diseases. No criminal charges have been filed against them, and the FDA has not filed any civil charges either.”

The current political environment may hamper rather than facilitate progress on this front.

“We are currently in a pro-entrepreneurial, anti-regulatory environment, so the FDA is in the position of having to balance patient desires for new treatments, and approving treatments as quickly as possible, with the desire to shield patients from bad outcomes,” says Dr. Albini. “The FDA regulations that we have in place now may be adequate, but they need to be enforced. As far as I can tell from reading the legislation, it’s pretty obvious that these stem cell clinics are breaking the law, but someone has to begin prosecuting. Whether there is time, money, or political capital to do that may be another matter.” NRP

REFERENCES

1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-1147.
2. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;30;131(5):861-872.
3. Tachibana M, Amato P, Sparman M, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell. 2013;153(6):1228-1238.
4. Grady D. Patients lose sight after stem cells are injected into their eyes. The New York Times; March 15, 2017. Article available at: https://www.nytimes.com/2017/03/15/health/eyes-stem-cells-injections.html?_r=0 ; last accessed May 12, 2017.
5. Kuriyan AE, Albini T, Townsend JH, et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376:1047-1053.
6. Marks PW, Witten CM, Califf RM. Clarifying stem-cell therapy’s benefits and risks. N Engl J Med. 2017;376:1007-1009.