Recent positive outcomes from scientifically rigorous studies of the use of cell therapy for retinal disorders have sparked interest in this burgeoning field. Schwartz and colleagues demonstrated safety and some positive anatomic and visual changes after subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelium (RPE) cells for Stargardt’s macular dystrophy and age-related macular degeneration (AMD).1 Multiple other published studies using dissociated cells and stem cell-derived RPE sheets have demonstrated safety as well.2–5

While scrupulous scientific research is ongoing for evidence in support of cell therapy, “cell therapy” clinics within the United States offer “cell therapy” for a multitude of medical conditions, including ophthalmologic disease processes. Despite not being approved by the Food and Drug Administration, patients are readily able to gain access through direct-to-consumer online marketing. Some patients are lured into a false sense of security as these sites claim to participate in clinical studies and list them on the Clinicaltrials.gov website. However, some patients do not realize that the website is a repository for all ongoing clinical trials, and not an endorsement of the listed studies.

Multiple cases have reported the devastating complications that have occurred in patients who received treatments at these “cell therapy” clinics.7–10 In one such published report, three patients were recorded to have vision deteriorate from a range of 20/30 to 20/50 in their better seeing eye to 20/200 to no light perception following bilateral intravitreal injections of adipose-derived stem cells. This was the result of multiple complications, including retinal and vitreous hemorrhages, retinal detachments with proliferative vitreoretinopathy, and zonular weakness, after injections.7

Our recent presentation at the American Society of Retina Specialists 2018 meeting focused on assessing the scope of the “cell therapy” clinics that advertise treatments for ocular conditions. We performed a systematic, keyword-based Internet search to assess the magnitude of this concern. Our goal was to identify U.S.-based businesses that perform online direct-to-consumer marketing of “cell therapy” for ophthalmologic diseases. Ultimately, we discovered approximately 40 companies that participate in this type of activity. These companies were located across the nation. The states with the most “cell therapy” clinics included California, Florida, and Illinois. Companies offered multiple sources for “cells” including autologous adipose-derived stem cells and bone marrow-derived stem cells, allogenic bone marrow-derived stem cells, amniotic stem cells, placental stem cells, peripheral blood-derive stem cells, umbilical cord blood stem cells, and xeno cells. The companies advertise delivering these cells by a variety of methods, but the most commonly listed route was intravenously. More ocular specific routes included intravitreal injections, retrobulbar injections, and eye drops. The cost of these services ranged from $4,000 to $10,500, however, some reports have listed prices upwards of $50,000.11

Due to the growing problem of “cell therapy” clinics, the American Academy of Ophthalmology issued a statement in 2016 warning the public that these treatments are not approved by the FDA, nor are the risks completely understood. Initially, these companies claimed that the use of autologous cells required minimal manipulation and were considered homologous use, so they did not fall under the jurisdiction of the FDA.11,12 However, the FDA issued a draft guidance clarifying the definition of “minimally manipulated” in December 2014 and a draft guidance specifying limitations of homologous use in October 2015. These statements served to delineate that the use of autologous stem cells do fall under FDA regulation. Since then, the FDA has issued warnings to two “cell therapy” clinics.

The efficacy and safety of cell therapies for ophthalmology require further scientific investigation to build on the recent early phase scientific studies. In the interim, it is important that patients, as well as clinicians, are educated about the practices and risks of treatments at “cell therapy” clinics.

References

1. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet Lond Engl. 2015 Feb 7;385(9967):509–16.

2. Ho AC, Chang TS, Samuel M, Williamson P, Willenbucher RF, Malone T. Experience With a Subretinal Cell-based Therapy in Patients With Geographic Atrophy Secondary to Age-related Macular Degeneration. Am J Ophthalmol. 2017 Jul 1;179:67–80.

3. Cruz L da, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, et al. Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018 Apr;36(4):328–37.

4. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017 Mar 16;376(11):1038–46.

5. Kashani AH, Lebkowski JS, Rahhal FM, Avery RL, Salehi-Had H, Dang W, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med. 2018 Apr 4;10(435):eaao4097.

6. ClinicalTrials.gov [Internet]. [cited 2018 Jul 14]. Available from: https://clinicaltrials.gov/

7. Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE, et al. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. N Engl J Med. 2017 16;376(11):1047–53.

8. Rong AJ, Lam BL, Ansari ZA, Albini TA. Vision Loss Secondary to Autologous Adipose Stem Cell Injections: A Rising Problem. JAMA Ophthalmol. 2018 Jan 1;136(1):97–9.

9. Leung EH, Flynn HW, Albini TA, Medina CA. Retinal Detachment After Subretinal Stem Cell Transplantation. Ophthalmic Surg Lasers Imaging Retina. 2016 01;47(6):600–1.

10. Saraf SS, Cunningham MA, Kuriyan AE, Read SP, Rosenfeld PJ, Flynn HW, et al. Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived “Stem Cells” in a Patient With Exudative Macular Degeneration. Ophthalmic Surg Lasers Imaging Retina. 2017 Sep 1;48(9):772–5.

11. Taylor-Weiner H, Graff Zivin J. Medicine’s Wild West — Unlicensed Stem-Cell Clinics in the United States. N Engl J Med. 2015 Sep 10;373(11):985–7.

12. Parke DW, Lum F, McLeod SD. Stem Cell Treatment: Think Twice If They Ask for Payment. Ophthalmology. 2016 Oct;123(10S):S62–3.

13. Parke DW, Lum F, McLeod SD. Stem Cell Treatment: Think Twice If They Ask for Payment. Ophthalmology. 2016 Oct;123(10S):S62–3.