Cell Therapy for Retinal and Optic Nerve Diseases: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Ophthalmology
Contributor:
j Pastor

Retinal Degenerative diseases and Optic Nerve diseases have been largely characterized and are considered leading causes of blindness worldwide.  One of the hopes for possible treatments lies in cell therapy. This entry updates those that are the subject of clinical trials and therefore have a better chance of reaching clinical use. The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice.

  • retinal diseases
  • optic nerve diseases
  • cell replacement
  • stem cells
  • neuroprotection

1. Introduction

 IOBA (Eye Institute) of the University of Valladolid, Valladolid, is considered a reference in Spain in applied research in cell therapy, mainly with allogenic mesemchymal stem cells derived from bone marrow (BM-MSC).Our studies began on the ocular Surface diseases 15 years ago, and finally clinical trials have been carried out for the treatment of limbal insufficiency, which are the first in the world.(ClinicalTrials.gov Identifier: NCT0388456). Furthermore, the Spanish Medicines Agency  (AEMPS) has been requested to grant "authorization for use" to increase our treatment capacity.

But for the last five years they have also been working on optic nerve pathology. In this field, a phase II clinical trial has been carried out, with five patients affected by acute non-arteritic anterior optic neuropathy. (ClinicalTrials.gov Identifier: NCT03173638). This disease has been selected, although it is rare, because it does not have any treatment, its natural history does not show significant improvements and depending on the series, up to 25% of patients suffer an involvement of the fellow eye in a period of 5 years. .

The preliminary results, after 6 months of follow uop, look very promising and a multicenter study is now expected to be completed to recruit more patients. In the meantime, we have found it opportune to review and update all the existing literature, with an eye on the transfer to the clinic, analyzing clinical trials and their safety and efficacy.

The above mentioned review provides an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases. Althought we are concentrated in BM-MSC paper describes the available cell sources and the challenges involved in real clinical practice.

Sources include human fetal stem cells, allogenic cadaveric  stem  cells,  human  CNS  stem  cells,  ciliary  pigmented  epithelial  cells,  limbal  stem  cells,  retinal  progenitor  cells  (RPCs),  human  pluripotent  stem  cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). The routes of administration of the cells are also discussed, emphasizing their pros and especially their cons. It seems that the most used route is the direct intravitreal route, of which ophthalmologists have great experience.

Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long‐term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical  translation  of  cell‐based  therapy,  including  (1)  the  ability  to  enrich  for  specific  retinal  subtypes;  (2) cell survival;  (3)  cell delivery, which  may need  to  incorporate a scaffold to induce correct cell polarization, (4) the requirement of complex intraocular surgical techniques wich are potential source of severe complications  (5)  the  evaluation  of  the  risk  of  tumor  formation  caused by  the undifferentiated  stem  cells and prolific  progenitor cells.  For this reason, our group is focused on the use of their paracrine capacities as sources of growth factors, which can be a good alternative to other possibilities of neuroprotection. As mentioned our group in focused in mesemchymal stem cells. MSCs  may  originate  from  amniotic  fluid  or  the umbilical  cord, although they are  mainly obtained from two developmentally mature organs: bone marrow mesenchymal stem  cells  (BMMSCs)  and  adipose  mesenchymal  stem  cells  (ADMSCs).  The  latter  are  much  more  abundant  and  easier  to  harvest  from  alive  donors,  with  less  invasive procedures. Moreover, they expand faster and demonstrate a higher immunomodulatory capacity  than  BMMSCs.  MSCs  have  been  shown  to  have  anti‐inflammatory,  immunosuppressive,  angiogenic  and  antiapoptotic  or  neuroprotective  effects. We use BM-MSCs because one of the MSV lines is accepted by the AEMPS as an investigational product and there is a great experience in human clinical application in various diseases. But we think that adipose tissue-derived cells AD-MSC may also be a great option. The existent works based on iPSC are also discussed at length, noting some of the problems that they present for their transfer to the clinic, such as their high risk of gene mutations.

Regarding the diseases that are the object of clinical trials, they are mainly the dry forms of age-related macular degeneration (AMD), Stargardt's disease, retinitis pigmentosa and other less frequent ones such as choroideremia.

Regarding diseases of the optic nerve, there are few well-structured clinical trials, with very varied pathologies, with multiple routes of administration of stem cells. In this way it is very difficult to establish if there really are some therapeutic possibilities.

In any case, the studies both in retinal and optic nerve diseases are mostly in phase I / II and there are also some proofs of concept.

The real fact is that despite the large number of clinical trials, there does not appear to have been a real transfer to clinical practice so far.

In summary, and although much progress has been made towards translating stem/progenitor cell technology into optimized therapies for retinal and optic nerve diseases,  the road to the clinic will be undeniably long. More defined differentiation protocols are required to improve  efficiency  and  to  obtain  high‐quality  enriched  retinal  cells  at  the  desire  state. Insights  into  human  retinal  development  with  the  advent  of  3D  cell  culture techniques that mimic in vivo development may help in this regard. Moreover, the genetic modification  of  stem  cells  may  prove  to  be  a  viable  approach  to  generating  specific  populations of retinal cells that are able to produce some desirable cell products or to be used  after  correcting  a  disease‐causing  mutation. Furthermore, the challenge of the immune rejection of transplants needs to be addressed. Currently, stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as inhibition of proliferation and/or differentiation in vitro (with the exception of the RPE) and limited long‐term survival and functioning of grafts in  vivo. 

Despite the challenges, stem/progenitor  cells  represent  the  most  promising  strategy  for  retinal  and  optic  nerve  disease  treatment  in  the  near  future,  and  therapeutics  assisted  by  gene  techniques,  neuroprotective compounds and artificial devices can be applied to fulfil clinical needs. Finally,  the  collaboration  of  various  experts  in  engineering, cell biology, genetics and clinical medicine seems essential for the development of successful cell therapies. 

2. Conclusions

Much progress has been made towards translating stem/progenitor cell technology into optimized therapies for retinal and optic nerve diseases demonstrating safety and efficacy. However, scientists need to work in more defined differentiation protocols and immune  rejection  of  transplants,  as  well  as  provide  insights  into  human  retinal  development and genetic modification of stem cells. 

3. Application

This entry can be useful for the most basic researchers who want to orient their work towards a transfer to the clinic. It can also be useful for clinicians whose objectives are to develop advanced therapies and within them cell therapy, opening new horizons as unique or complementary treatments to existing ones. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics13060865

References

  1. Marí Sonia Labrador-Velandia; Sara Alvarez-Sanchez A Luz Alonso-Alonso; Sara Alvarez-Sanchez; Irene Carretero-Barrio Lez-Zamora; Irene Carretero-Barrio; Ivá Carlos Pastor; Girish Kumar Srivastava N Fernandez-Bueno; Girish Kumar Srivastava; Mesenchymal stem cell therapy in retinal and optic nerve diseases: An update of clinical trials. World Journal of Stem Cells 2016, 8, 376-383, 10.4252/wjsc.v8.i11.376.
  2. Lin Fu; Sum Sum Kwok; Yau Kei Chan; Jimmy Shiu Ming Lai; Weihua Pan; Li Nie; Kendrick Co Shih; Therapeutic Strategies for Attenuation of Retinal Ganglion Cell Injury in Optic Neuropathies: Concepts in Translational Research and Therapeutic Implications. BioMed Research International 2019, 2019, 1-10, 10.1155/2019/8397521.
  3. Darcie Moore; Jeffrey Goldberg; Four Steps to Optic Nerve Regeneration. Journal of Neuro-Ophthalmology 2010, 30, 347-360, 10.1097/wno.0b013e3181e755af.
  4. Bireswar Laha; Ben K. Stafford; Andrew D. Huberman; Regenerating optic pathways from the eye to the brain. Science 2017, 356, 1031-1034, 10.1126/science.aal5060.
  5. Bo Young Chun; Dean M. Cestari; Advances in experimental optic nerve regeneration. Current Opinion in Ophthalmology 2017, 28, 558-563, 10.1097/icu.0000000000000417.
  6. Margaret Maes; Cassandra L. Schlamp; Robert W. Nickells; BAX to basics: How the BCL2 gene family controls the death of retinal ganglion cells. Progress in Retinal and Eye Research 2017, 57, 1-25, 10.1016/j.preteyeres.2017.01.002.
  7. Puertas‐Neyra, K.; Usategui‐Martín, R.; Coco, R.M.; Fernandez‐Bueno, I.; Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative disease. Neural Regen. Re 2020, 15, , 1631–16, 10.4103/1673‐5374.276324.
  8. Wang, Y.; Tang, Z.; Gu, P.; Stem/progenitor cell‐based transplantation for retinal degeneration: A review of clinical trials.. Cell Death Dis. 2020, 11, 793, 10.1038/s41419‐020‐02955‐3.
  9. Tang, Z.; Zhang, Y.; Wang, Y.; Zhang, D.; Shen, B.; Luo, M.; Gu, P.; Progress of stem/progenitor cell‐based therapy for retinal degeneration. J. Transl. Med. 2017, 15, 99, 10.1186/s12967‐017‐1183‐y.
  10. Megaw,  R.;   Dhillon,  B. ; Stem  cell  therapies  in  the  management  of  diabetic  retinopathy. . Curr.  Diab.  Rep. 2014, 14, 498, 10.1007/s11892‐014‐0498‐9.
  11. Eric Souied; Jose Pulido; Giovanni Staurenghi; Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. New England Journal of Medicine 2017, 377, 792-793, 10.1056/nejmc1706274.
  12. Sacha Reichman; Amélie Slembrouck; Giuliana Gagliardi; Antoine Chaffiol; Angélique Terray; Céline Nanteau; Anais Potey; Morgane Belle; Oriane Rabesandratana; Jens Duebel; et al. Generation of Storable Retinal Organoids and Retinal Pigmented Epithelium from Adherent Human iPS Cells in Xeno‐Free and Feeder‐Free Conditions. STEM CELLS 2017, 35, 1176-1188, 10.1002/stem.2586.
  13. Park, S.S.; Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion.. Investig. Ophthalmol. Vis. Sci. 2016, 57, 1, 10.1167/iovs.15‐17594.
  14. Nutan Prasain; Man Ryul Lee; Sasidhar Vemula; Jonathan Luke Meador; Momoko Yoshimoto; Michael J Ferkowicz; Alexa Fett; Manav Gupta; Brian M Rapp; Mohammad Reza Saadatzadeh; et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony–forming cells. Nature Biotechnology 2014, 32, 1151-1157, 10.1038/nbt.3048.
  15. Tea Soon Park; Imran Bhutto; Ludovic Zimmerlin; Jeffrey S. Huo; Pratik Nagaria; Diana Miller; Abdul Jalil Rufaihah; Connie Talbot; Jack Aguilar; Rhonda Grebe; et al. Vascular progenitors from cord blood-derived induced pluripotent stem cells possess augmented capacity for regenerating ischemic retinal vasculature.. Circulation 2014, 129, 359-72, 10.1161/CIRCULATIONAHA.113.003000.
  16. A Safwat; D Sabry; A Ragiae; E Amer; Rh Mahmoud; Rm Shamardan; Adipose mesenchymal stem cells–derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits. Journal of Circulating Biomarkers 2018, 7, 1, 10.1177/1849454418807827.
  17. Alexander, P.; Thomson, H.A.; Luff, A.J.; Lotery, A.J.; Retinal pigment epithelium transplantation: Concepts, challenges, and future prospects.. Eye 2015, 29, 992–1002, 10.1038/eye.2015.89..
  18. Uyama, H.; Mandai, M.; Takahashi, M.; Stem Cell‐Based Therapies for Retinal Degenerative Diseases: Current Challenges in the Establishment of New Treatment Strategies.. Dev. Growth Differ. 2020, 63, 59–71, 10.1111/dgd.12704..
  19. 46. Satarian, L.; Nourinia, R.; Safi, S.; Kanavi, M.R.; Jarughi, N.; Daftarian, N.; Arab, L.; Aghdami, N.; Ahmadieh, H.; Baharvand, H; et al. Intravitreal injection of bone marrow mesenchymal stem cells in patients with advanced retinitis pigmentosa; a safety study.. J. Ophthalmic Vis. Res.  2017, 12, 58–64, 10.4103/2008‐322X.200164.
  20. Schwartz,  S.D.;   Hubschman,  J.‐P.;   Heilwell,  G.;   Franco‐Cardenas,  V.;   Pan,  C.K.;   Ostrick,  R.M.;   Mickunas,  E.;   Gay,  R.; Klimanskaya, I.; Lanza, R.; et al. Embryonic stem cell trials for macular degeneration: A preliminary report. . Lancet 2012, 379, 713–720, 10.1016/S0140‐6736(12)60028‐2.
  21. Mehat, M.S.; Sundaram, V.; Ripamonti, C.; Transplantation of Human Embryonic Stem Cell‐Derived Retinal Pigment Epithelial Cells in Macular Degeneration. . Ophthalmology 2018, 125, 1765–1775,, 10.1016/j.ophtha.2018.04.037..
  22. Hiroyuki Kamao; Michiko Mandai; Satoshi Okamoto; Noriko Sakai; Akiko Suga; Sunao Sugita; Junichi Kiryu; Masayo Takahashi; Characterization of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets Aiming for Clinical Application. Stem Cell Reports 2014, 2, 205-218, 10.1016/j.stemcr.2013.12.007.
  23. Lyndon Da Cruz; Kate Fynes; Odysseas Georgiadis; Julie Kerby; Yvonne H Luo; Ahmad Ahmado; Amanda Vernon; Julie T Daniels; Britta Nommiste; Shazeen M Hasan; et al. Phase 1 clinical study of an embryonic stem cell–derived retinal pigment epithelium patch in age-related macular degeneration. Nature Biotechnology 2018, 36, 328-337, 10.1038/nbt.4114.
  24. Cuiping Zhao; Qingjie Wang; Sally Temple; Stem cell therapies for retinal diseases: recapitulating development to replace degenerated cells. Development 2017, 144, 1368-1381, 10.1242/dev.133108.
  25. David Terrell; Jason Comander; Current Stem-Cell Approaches for the Treatment of Inherited Retinal Degenerations. Seminars in Ophthalmology 2019, 34, 287-292, 10.1080/08820538.2019.1620808.
  26. Clayton P. Santiago; Casey J. Keuthan; Sanford L. Boye; Shannon E. Boye; Aisha A. Imam; John D. Ash; A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration. Molecular Therapy 2018, 26, 2407-2417, 10.1016/j.ymthe.2018.07.016.
  27. Ricardo Usategui-Martín; Kevin Puertas-Neyra; María-Teresa García-Gutiérrez; Manuel Fuentes; José Carlos Pastor; Ivan Fernandez-Bueno; Human Mesenchymal Stem Cell Secretome Exhibits a Neuroprotective Effect over In Vitro Retinal Photoreceptor Degeneration. Molecular Therapy - Methods & Clinical Development 2020, 17, 1155-1166, 10.1016/j.omtm.2020.05.003.
  28. Sonia Labrador-Velandia; Maria Luz Alonso-Alonso; Salvatore Di Lauro; Maria Teresa García-Gutierrez; Girish K. Srivastava; J Carlos Pastor; Ivan Fernandez-Bueno; Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures. Experimental Eye Research 2019, 185, 107671, 10.1016/j.exer.2019.05.011.
  29. 98. Labrador Velandia, S.; Di Lauro, S.; Alonso‐Alonso, M.L.; Tabera Bartolome, S.; Srivastava, G.K.; Pastor, J.C.; Fernandez‐Bueno, I; Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. . Graefes Arch. Clin. Exp. Ophthalmol. 2018, 256, 125–134, 10.1007/s00417‐017‐3842‐3..
  30. Sugita, S.; Mandai, M.; Hirami, Y.; Takagi, S.; Maeda, T.; Fujihara, M.; Matsuzaki, M.; Yamamoto, M.; Iseki, K.; Hayashi, N.; et al. HLA‐Matched Allogeneic iPS Cells‐Derived RPE Transplantation for Macular Degeneration. J. . Clin. Med. 20 2020, 9, 2217, 10.3390/jcm9072217.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback