Cell Therapy for Age-Related Macular Degeneration: A New Vision for the Bone Marrow?
Authors: Alexander V. Ljubimov
Journal: Molecular Therapy (2017)

In this issue of Molecular Therapy, Qi et al.1Qi X. Pay S.L. Yan Y. Thomas Jr., J. Lewin A.S. Chang L.J. Grant M.B. Boulton M.E. Systemic injection of RPE65-programmed bone marrow-derived cells prevents progression of chronic retinal degeneration.Mol. Ther. 2017; 25 (this issue): 917-927Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar report that a cell therapy can improve retinal structure and vision in a mouse model of age-related macular degeneration (AMD). AMD is the leading cause of severe and irreversible central vision loss in the elderly, affecting over 1.7 million Americans.2Friedman D.S. O'Colmain B.J. Muñoz B. Tomany S.C. McCarty C. de Jong P.T. Nemesure B. Mitchell P. Kempen J. Eye Diseases Prevalence Research GroupPrevalence of age-related macular degeneration in the United States.Arch. Ophthalmol. 2004; 122: 564-572Crossref PubMed Scopus (77) Google Scholar The authors made use of bone marrow-derived cells (BMDCs) that had been engineered to stably express RPE65 protein (BMDC-RPE65). RPE65 is a marker of the retinal pigment epithelium (RPE) that degenerates in AMD. Systemically administered, BMDC-RPE65 homed to the diseased retina and were incorporated into the chronically damaged RPE layer, which led to correction of RPE pathology. Importantly, the therapy preserved vision, as documented by two functional tests. The Qi et al.1Qi X. Pay S.L. Yan Y. Thomas Jr., J. Lewin A.S. Chang L.J. Grant M.B. Boulton M.E. Systemic injection of RPE65-programmed bone marrow-derived cells prevents progression of chronic retinal degeneration.Mol. Ther. 2017; 25 (this issue): 917-927Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar study shows the clear potential of BMDCs for treating AMD and other retinal degenerations involving RPE and attests to the feasibility of autologous AMD treatment using this new exciting approach. Early/dry AMD is the atrophic form found in 85% of AMD patients and is characterized by progressive loss of RPE, with formation of toxic complement and lipid deposits, and may gradually extend to large areas. Loss of RPE in the central retina is followed by subsequent degeneration of photoreceptors and loss of central vision (Figure 1). Late/wet AMD is the most severe form of the disease, with rupture of the Bruch's membrane separating RPE from trophic choriocapillaris vessels, and an ensuing subretinal neovascularization from the choriocapillaris that is largely driven by vascular endothelial growth factor (VEGF). Anti-VEGF therapies are fairly efficient at counteracting this neovascularization and are currently the mainstream treatment for wet AMD.3Fields M. Cai H. Gong J. Del Priore L. Potential of induced pluripotent stem cells (iPSCs) for treating age-related macular degeneration (AMD).Cells. 2016; 5: 44Crossref Scopus (25) Google Scholar However, no treatment has been effective so far for the more common dry form. Because of the degenerative nature of dry AMD, significant efforts have been made lately to develop cell replacement therapies. These approaches aim to replace diseased RPE functions and keep the remaining photoreceptors healthy. RPE cell transplantation represents a realistic strategy,4Binder S. Stanzel B.V. Krebs I. Glittenberg C. Transplantation of the RPE in AMD.Prog. Retin. Eye Res. 2007; 26: 516-554Crossref PubMed Scopus (233) Google Scholar, 5da Cruz L. Chen F.K. Ahmado A. Greenwood J. Coffey P. RPE transplantation and its role in retinal disease.Prog. Retin. Eye Res. 2007; 26: 598-635Crossref PubMed Scopus (201) Google Scholar because it involves a single cell type and does not require the re-establishment of neural networks. Freshly isolated and cultured RPE cells have been transplanted into the subretinal space of animal models and AMD subjects.4Binder S. Stanzel B.V. Krebs I. Glittenberg C. Transplantation of the RPE in AMD.Prog. Retin. Eye Res. 2007; 26: 516-554Crossref PubMed Scopus (233) Google Scholar, 5da Cruz L. Chen F.K. Ahmado A. Greenwood J. Coffey P. RPE transplantation and its role in retinal disease.Prog. Retin. Eye Res. 2007; 26: 598-635Crossref PubMed Scopus (201) Google Scholar, 6Rowland T.J. Buchholz D.E. Clegg D.O. Pluripotent human stem cells for the treatment of retinal disease.J. Cell. Physiol. 2012; 227: 457-466Crossref PubMed Scopus (72) Google Scholar However, the results have only been modest in humans,4Binder S. Stanzel B.V. Krebs I. Glittenberg C. Transplantation of the RPE in AMD.Prog. Retin. Eye Res. 2007; 26: 516-554Crossref PubMed Scopus (233) Google Scholar, 5da Cruz L. Chen F.K. Ahmado A. Greenwood J. Coffey P. RPE transplantation and its role in retinal disease.Prog. Retin. Eye Res. 2007; 26: 598-635Crossref PubMed Scopus (201) Google Scholar which has been attributed to the invasive delivery of cells to the subretinal space of only late-stage patients already exhibiting marked loss of RPE and photoreceptors. Additionally, the aging retina may be a poor host for transplanted cells. A different approach involves RPE derived from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). This approach has been tested in animal models with some success. The paucity of animal models that closely mimic the human disease remains a hurdle. Other than primates, most animals lack a macula (a small central yellow area of the retina that provides high acuity vision), making such models just an approximation of the human condition. Nonetheless, animal studies have been translated into clinical trials of this cell replacement approach, but, so far, with inconclusive results.3Fields M. Cai H. Gong J. Del Priore L. Potential of induced pluripotent stem cells (iPSCs) for treating age-related macular degeneration (AMD).Cells. 2016; 5: 44Crossref Scopus (25) Google Scholar Additionally, ESC use is fraught with ethical concerns. iPSCs might form teratomas due to incomplete differentiation or spontaneously mutate, which has caused a temporary halt of one clinical trial in Japan. Qi et al.1Qi X. Pay S.L. Yan Y. Thomas Jr., J. Lewin A.S. Chang L.J. Grant M.B. Boulton M.E. Systemic injection of RPE65-programmed bone marrow-derived cells prevents progression of chronic retinal degeneration.Mol. Ther. 2017; 25 (this issue): 917-927Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar took a different approach that avoided the complex reprogramming of ESCs or iPSCs into RPE or subretinal injections. Instead, they exploited the known ability of BMDCs to enter the circulation and home to sites of tissue injury. Additionally, BMDCs have been proven safe and efficient in over 30 years of human bone marrow transplantations. Adult BMDCs retain the capacity to differentiate toward a number of non-hematopoietic lineages, such as those of heart, bone, liver, pancreas, muscle, and central nervous system.7Dawn B. Bolli R. Adult bone marrow-derived cells: regenerative potential, plasticity, and tissue commitment.Basic Res. Cardiol. 2005; 100: 494-503Crossref PubMed Scopus (100) Google Scholar In the eye, BMDCs can take on several characteristics of vascular endothelial cells, pericytes, astrocytes, microglia, and RPE. Although these events are relatively rare in vivo, they likely occur in sufficient frequency to affect tissue physiology. This type of BMDC plasticity represents a key aspect of the reparative process following tissue damage. To cause BMDCs to preferentially home to RPE lesions, Qi et al.1 used a "single factor programming" strategy. BMDCs were programmed ex vivo by inserting a stable transgene using a lentiviral vector carrying the RPE65 gene coding for an RPE-specific 65 kDa protein, which is an important component of the visual cycle responsible for regeneration of visual pigment. The authors tested the impact of administering these genetically modified cells systemically, which is safer than subretinal injections, on retinal structure and function, as well as on vision. Using a mouse model with chemical ablation of the RPE cell layer, the authors previously reported that systemically administered BMDCs engineered to express RPE65 were able to home to the subretinal space, differentiate into RPE-like cells, and restore a functional RPE layer and vision.8Sengupta N. Caballero S. Sullivan S.M. Chang L.J. Afzal A. Li Calzi S. Kielczewski J.L. Prabarakan S. Ellis E.A. Moldovan L. et al.Regulation of adult hematopoietic stem cells fate for enhanced tissue-specific repair.Mol. Ther. 2009; 17: 1594-1604Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar However, the acute chemical ablation model does not recapitulate the conditions and signals that occur in human subjects with a chronically diseased tissue, emphasizing the importance of the current study. In their new study, Qi et al.1Qi X. Pay S.L. Yan Y. Thomas Jr., J. Lewin A.S. Chang L.J. Grant M.B. Boulton M.E. Systemic injection of RPE65-programmed bone marrow-derived cells prevents progression of chronic retinal degeneration.Mol. Ther. 2017; 25 (this issue): 917-927Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar used a mouse model better approximating dry AMD: the superoxide dismutase 2 (Sod2) knockdown generated by an adeno-associated viral vector-delivered ribozyme. The Sod2 ribozyme causes increased expression of oxidative damage markers, RPE degeneration, Bruch's membrane thickening, shortening and disorganization of the photoreceptor outer and inner segments, and loss of electroretinograph response.9Justilien V. Pang J.J. Renganathan K. Zhan X. Crabb J.W. Kim S.R. Sparrow J.R. Hauswirth W.W. Lewin A.S. SOD2 knockdown mouse model of early AMD.Invest. Ophthalmol. Vis. Sci. 2007; 48: 4407-4420Crossref PubMed Scopus (194) Google Scholar These changes are reminiscent of what occurs in human dry AMD. The authors show that RPE65-transduced BMDCs "home" to areas of chronic RPE injury, specifically to the subretinal space, where they assimilate with the existing RPE. Once there, the cells are influenced by the microenvironment and assume characteristics of RPE cells. In contrast to cells expressing a control LacZ transgene, BMDC-RPE65 corrected RPE pathology and increased the thickness of the neural retina. Electroretinography and optokinetic responses confirmed that visual function was significantly improved in BMDC-RPE65-treated mice. Whereas RPE65-BMDC administration was most effective in early disease, restoring visual function and retinal morphology to near normal, it was less effective in late-stage disease, indicating that therapy must start as early as possible. The study opens new avenues for future therapy in a chronic disease, such as AMD, where the injured tissue may not be sending out a sufficiently loud distress signal to circulating BMDCs. Nevertheless, the study shows that, even at early stages, the molecular signals from a diseased retina/RPE, such as CXCL1210Kucia M. Ratajczak J. Reca R. Janowska-Wieczorek A. Ratajczak M.Z. Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury.Blood Cells Mol. Dis. 2004; 32: 52-57Crossref PubMed Scopus (216) Google Scholar and VEGF, may be sufficiently robust to call in the engineered circulating BMDCs. We do not yet understand why the natural repair process fails in AMD patients and whether this inefficiency is related to older age. What we know now is that it may soon be possible to help to boost this response by delivering engineered autologous cells into circulation to help fight the disease. This would allow treating the disease while the retina still retains viable tissue surrounding the growing RPE lesions, which would likely provide a better clinical outcome. Although no early interventions exist to date, Qi et al.1Qi X. Pay S.L. Yan Y. Thomas Jr., J. Lewin A.S. Chang L.J. Grant M.B. Boulton M.E. Systemic injection of RPE65-programmed bone marrow-derived cells prevents progression of chronic retinal degeneration.Mol. Ther. 2017; 25 (this issue): 917-927Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar now offer the promise of this possibility for the future by exploiting natural repair mechanisms involving the bone marrow. Their work clearly demonstrates the success of a minimally invasive strategy that could be used early in the natural history of the disease. This work was supported by NIH grants R01 EY013431 and R01 EY023429 and grants from the Board of Governors Regenerative Medicine Institute. Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal DegenerationQi et al.Molecular TherapyJanuary 23, 2017In BriefBone marrow-derived cells (BMDCs) can differentiate into non-hematopoietic cell types, including retinal cells. Qi et al. describe the efficacy of systemically administered BMDCs, programmed by inserting a retina-specific transgene, to prevent visual loss in a mouse model of retinal degeneration. Full-Text PDF Open Access