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

The studies began on the ocular Surface diseases, 15 years ago, and finally where 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, loosults 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.

Regardingespite the 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 hallenges, stem/ II and there are also some proofs of concept.

The real fact is that despite the laroge 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,itor  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. 

Despitecells  represent  the  most  promising  the challenges, stem/progenitor  cells  represent  the  most  promising  strrategy  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]}