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Editors Selection IGR 22-2

Medical Treatment: Autologous Stem Cells for Visual Restoration

Thomas Johnson

Comment by Thomas Johnson on:

94583 Mesenchymal stem and non-stem cell surgery, rescue, and regeneration in glaucomatous optic neuropathy, Limoli PG; Limoli PG; Limoli C; Vingolo EM et al., Stem cell research & therapy, 2021; 12: 275


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Mesenchymal stem cells (MSCs) have long been purported to hold neuroprotective, neuro-enhancing, and neuroregenerative properties that could be leveraged for therapeutic transplantation.1-3 MSCs can be isolated from numerous sources including bone marrow and adipose tissue. Their innate multimodal paracrine activity following autologous transplantation makes MSCs appealing for treating neurodegenerative diseases throughout the central nervous system. Preclinical data in experimental animal models of glaucoma have demonstrated beneficial effects on injured retinal ganglion cells with mechanisms that include secretion of neurotrophic factors, cytokines, miRNA, and extracellular vesicles.4-9

Despite trials evaluating MSC transplantation for the treatment of myriad neurodegenerative conditions, convincing evidence supporting their clinical use has been underwhelming. Moreover, intraocular transplantation of MSCs and related adipose or bone-marrow derived cells in human patients has been documented to cause serious complications including epiretinal membrane formation, retinal detachment, choroidal neovascularization, and vision loss,10-13 highlighting a critical challenge in translating MSC therapy to ophthalmic disease. Limoli et al. have attempted to address this issue by developing a suprachoroidal transplantation technique enabling long-term delivery of secreted factors to the retina while sequestering the graft in a location that one hopes is safer than the vitreous cavity or subretinal space. As early investigations of suprachoroidal drug and vector delivery appear safe and efficacious,14 it is conceivable that suprachoroidal MSC transplantation might facilitate clinical translation of this neuroprotective treatment.

Limoli et al.'s approach involves autologous transplantation of a tripartite mixture of (1) adipose stromal cells contained within excised orbital fat; (2) adipose-derived stem cells from an abdominal fat aspirate; and (3) platelet rich plasma from a blood sample. The graft is inserted into the suprachoroidal space under a deep scleral flap with a hinge located eight mm from the inferotemporal limbus. It is concerning that this combination of cells has apparently not been tested in preclinical animal models, nor has the scientific basis or mechanism of beneficial activity for this mixture of multiple cell sources been specifically elucidated. Nonetheless, the approach has been trialed in a series of case reports that included small numbers of human patients with non-neovascular age-related macular degeneration,15,16 retinitis pigmentosa,17,18 and non-glaucomatous optic neuropathy.19 Across those reports, a total of 106 eyes underwent the procedure and no adverse events were documented.

The current non-randomized study included 35 eyes from 25 patients with glaucoma diagnosed on the basis of microperimetry and/or optical coherence tomography (OCT), of which 14 eyes were treated with suprachoroidal MSC transplantation. Twenty-one eyes from patients electing observation were used as a comparison group. Though indicators of glaucoma disease severity for subjects were not reported, inclusion criteria required a cup-to-disc ratio of < 0.6 suggesting that subjects had relatively mild glaucoma. Exclusion criteria included IOP > 15mmHg with medications, visual acuity worse than 1.0 LogMAR, refractive error ≥ six diopters, and prior intraocular surgery (though pseudophakic patients were reportedly included). An undisclosed number of patients were treated bilaterally.

The outcome of suprachoroidal MSC transplantation was assessed at six months. No adverse surgical events were reported. There was no difference in IOP between groups or after the intervention. Best corrected visual acuity was stable in the control group (0.1 LogMAR) and improved marginally from 0.21 to 0.16 logMAR following surgery. Mean microperimetric sensitivity in controls was 13.2dB at baseline and 12.6dB at six months. Sensitivity increased modestly following the surgical intervention from 10.0 to 11.1dB.

Limoli et al.'s innovative approach to suprachoroidal MSC transplantation is intriguing

Limoli et al.'s innovative approach to suprachoroidal MSC transplantation is intriguing. While the growing number of such transplants published in the literature without reported adverse events is perhaps encouraging, the surgical approach is highly invasive and may be prone to complications, especially in less experienced hands. It is possible that emerging suprachoroidal injection techniques being developed for drug delivery could provide a safer route for suprachoroidal MSC transplantation.14 Critically, the efficacy of this technique for conferring neuroprotection in glaucoma remains unclear and any potential for RGC regeneration (despite the article's title) was not assessed. This study was limited by: lack of precise glaucoma phenotype and severity characterizations for included subjects; comparison to a nonrandomized group of control patients who chose observation rather than surgical intervention and who retained better visual acuity and microperimetric sensitivity than the surgical group; ambiguous clinical significance of the small effects documented; and the use of visual acuity and microperimetric sensitivity as primary outcomes for a disease that affects central vision only at advanced stages and where standard automated perimetry and OCT of the retinal nerve fiber layer and macular ganglion cell complex are the established metrics for defining disease severity and progression.

While the glaucoma field is eagerly awaiting safe and efficacious neuroprotective interventions, clear evidence substantiating these characteristics for suprachoroidal MSC transplantation remain, for now, elusive. In an era of increasing stem cell tourism and performance of unproven stem cell transplants by unregulated clinics,20 rigorously performed and clinically informative trials are sorely needed.

References

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  2. Ng TK, Fortino VR, Pelaez D, Cheung HS. Progress of mesenchymal stem cell therapy for neural and retinal diseases. World J Stem Cells. 2014;6(2):111-119.
  3. Holan V, Palacka K, Hermankova B. Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials. Cells. 2021;10(3).
  4. Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010;51(4):2051-2059.
  5. Johnson TV, DeKorver NW, Levasseur VA, et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain. 2014;137:503-519.
  6. Mead B, Amaral J, Tomarev S. Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Invest Ophthalmol Vis Sci. 2018;59(2):702-714.
  7. Manuguerra-Gagne R, Boulos PR, Ammar A, et al. Transplantation of Mesenchymal Stem Cells Promotes Tissue Regeneration in a Glaucoma Model Through Laser- Induced Paracrine Factor Secretion and Progenitor Cell Recruitment. Stem Cells. 2013;31(6):1136-1148.
  8. Mead B, Tomarev S. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Translat Med. 2017;6(4):1273-1285.
  9. Harrell CR, Fellabaum C, Arsenijevic A, Markovic BS, Djonov V, Volarevic V. Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of Glaucoma. Stem Cells Int. 2019;2019.
  10. Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y. Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: A phase I clinical safety study. Stem Cell Res Ther. 2016;7(1):178.
  11. Kuriyan AE, Albini TA, Townsend JH, et al. Vision Loss after Intravitreal Injection of Autologous 'Stem Cells' for AMD. New England Journal of Medicine. 2017;376(11):1047-1053.
  12. Saraf SS, Cunningham MA, Kuriyan AE, et al. Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived 'Stem Cells' in a Patient With Exudative Macular Degeneration. OSLI Retina. 2017;48(9):772-775.
  13. Leung EH, Flynn HW, Albini TA, Medina CA. Retinal Detachment After Subretinal Stem Cell Transplantation. OSLI Retina. 2016;47(6):600-601.
  14. Chiang B, Jung JH, Prausnitz MR. The suprachoroidal space as a route of administration to the posterior segment of the eye. Adv Drug Deliv Rev. 2018;126:58-66.
  15. Limoli PG, Vingolo EM, Limoli C, Scalinci SZ, Nebbioso M. Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report. J Vis Exp. 2018(132).
  16. Limoli PG, Limoli C, Vingolo EM, Scalinci SZ, Nebbioso M. Cell surgery and growth factors in dry age-related macular degeneration: visual prognosis and morphological study. Oncotarget. 2016;7(30):46913-46923.
  17. Limoli PG, Vingolo EM, Limoli C, Nebbioso M. Stem Cell Surgery and Growth Factors in Retinitis Pigmentosa Patients: Pilot Study after Literature Review. Biomedicines. 2019;7(4).
  18. Limoli PG, Limoli CSS, Morales MU, Vingolo EM. Mesenchymal stem cell surgery, rescue and regeneration in retinitis pigmentosa: clinical and rehabilitative prognostic aspects. Restor Neurol Neurosci. 2020;38(3):223-237.
  19. Oner A, Gonen ZB, Sevim DG, Sinim Kahraman N, Unlu M. Six-month results of suprachoroidal adipose tissue-derived mesenchymal stem cell implantation in patients with optic atrophy: a phase 1/2 study. Int Ophthalmol. 2019;39(12):2913-2922.
  20. The_PEW_Charitable_Trusts. Harms Linked to Unapproved Stem Cell Interventions Highlight Need for Greater FDA Enforcement In: Health Care Products: Research and Analysis. Editor: Richardson L, 2021: 1-34. harms-linked-to-unapproved-stem-cell-interventionshighlight- need-for-greater-fda-enforcement.pdf. Accessed 12/12/2021


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