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.
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.
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.
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.