| Background Retinal pigmentosa(RP)is a kind of hereditary disease with the photoreceptors and retinal pigmented epithelium(RPE)degeneration.The clinical symptoms include progressive night blindness,progressive visual field defect,bone spicule-shaped pigment deposits,sallow color of the optic nerve,and stiff blood vessels.RP is a severe blinding diseases that significantly affect the visual function and living quality.However,there is no efficacious treatment for RP at present.In many trial therapy for advanced RP,the most prospective novel approach is stem cells implantation.It is reported that a number of clinical trials have been carrying out of transplantation mesenchymal stem cell for the retinal degenerative diseases,such as age-related macular degeneration,retinitis pigmentosa and Stargardt disease.The safety and feasibility of mesenchymal stem cell-based therapy has been proved in clinical application for autoimmune diseases,vascular diseases and organ transplantation.Nevertheless,the limitation of mesenchymal stem cells for the particularly difficult to obtained from the marrow and adipose tissue has drawn more attention now.Meanwhile,a novel stem cells,Umbilical cord mesenchymal stem cell(UC-MSC),has been introduced into clinical treatment trial at present.Compared the mesenchymal stem cells,more advantages were presented including acquired with noninvasive method,the possibility for differentiation into multiple lineages cells,damage repair,inflammation prohibition and nerve nutrition.In the current trial of UC-MSC,there are two main therapeutic methods: local implantation and systemic intravenous infusion(SII).However,the destruction for pigment epithelial cells,the most significant characteristics of RP,lead to no suitable space for local implantation.It is probably that the UC-MSC with SII could be the prospective,safety and efficacy clinical approach for RP.Based on the animal study of MSC SII through the tail vein of RCS rat,the MSC homing to the retinal ganglion cells layer and retinal neuron thickness could be observed.In many clinical treatment study of MSC,the security and immune tolerance have been confirmed.No rejection,infection and other adverse reactions had been reported ever.In this study,based on the confirmation of the efficacy of the UC-MSC SII on our previous animal experiment,we explored the safety and efficacy of UC-MSC TII for RP in clinical trial.Method Part Ⅰ:T he study of efficiency of the U C-MSC SII on RCS-rat.1.To observed the homing of US-MSC to the retina in 1 week and 2 week after US-MSC SII on RCS rats,the retina of RCS rats were taken out for retinal stretched preparation,frozen sections and immunohistochemical staining.To explore efficiency of the UC-MSC SII on RCS-rat,the measurement of the thickness for the outer nuclear layer(ONL)of retina and flash ERG have been carried out.2.To observe the concentration varies of the Brain-derived neurotrophic factor(BDNF),Interleukin-6(IL-6),Interleukin-10(IL-10),1 week and 2 week after US-MSC SII on RCS rats,the Enzyme-Linked Immunosorbent Assay has been done.Part Ⅱ: T he study of efficiency and security of the U C-MSC SII on clinical trial.1.Case inclusion criteria: affirmative diagnosis of voluntary RP patients who had sign the informed consent.This clinical trial has obtained approval of ethics committee of the southwest hospital of the third military medical university,the document NO: 2014-44.2.The follow-up of all the voluntary RP patients were performed on pre-UC-MSC SII,1 month post-UC-MSC SII,2 month post-UC-MSC SII,3 month post-UC-MSC SII,6 month post-UC-MSC SII.3.The evaluation of the security: Vital signs were observed before and after intravenous infusion of UC-MSC,and whether infection,fever,local pain,allergic reactions,infusion reactions and immunological rejection hanppened;blood,urine routine examination and liver and kidney function tests,chest X-ray examination;and whether there is pain or inflammation or loss of vision and so on.4.The evaluation of the efficacy: Best corrected visual acuity,fundus photography,fundus fluorescein angiography,optical coherence tomography,visual evoked potential and visual field examination were performed in follow up.National Eye Institute Visual Functioning Questionnaire,NEI_VQF-25 were performed,inflammatory factors and blood biochemical index were examined.Result Part Ⅰ: T he study of efficacy of the U C-MSC SII on RCS-rat.1.The observation on stretched retina with immunohistochemical staining indicated: the positive result could been observed in 1 week post UC-MSC SII in treatment group,however the false positive results were confirmed in 2 week post UC-MSC SII in treatment group;nevertheless,the negative results were presented in all the control group.The observation on retinal slices with immunohistochemical staining indicated: there was no conclusive evidence for the UC-MSC directional homing to retina after the UC-MSC SII at present.On the other hand,the thickness of ONL in treatment group was more statistical thicker than in control group(P<0.05).The Flash ERG indicated: amplitude of b wave in 1 week post UC-MSC SII in treatment group was more significant higher than the control group(P<0.05).The result that the transplanted cells could not homing to retinal,the ONL was effectively protected and visual function improved,indicated the efficiency of UC-MSC SII effective for RCS-rat because of possible neurotropic and immunoregulatory effects,rather than the stem cell replacement.2.In 1 or 2 week after UC-MSC SII on RCS-rat,BDNF in serum of treatment group was more higher than control group,and it is only significant at the second week.IL-10 in serum of treatment group was more significant higher than control group in 1week after UC-MSC SII,but no similar result was observed in 2 week after the treatment.In all the follow-up,the IL-6 in serum of treatment were less than control group.The observation indicated UC-MSC SII have neurotrophic and anti-inflammatory effect.Part Ⅱ: the study of efficacy and security of the U C-MSC SII on clinical trial.1.32 eyes of 16 patients were included in this study.2.All the patients have been finished the UC-MSC SII,one patient loss to follow-up in 2 month,another patient loss to follow-up in 6 month.The other patients finished all the follow-up 3.The evaluation of the security: Vital signs totally smooth before and after intravenous infusion of UC-MSC,no one suffered infection,fever,local pain,allergic reactions,infusion reactions and immunological rejection;blood,urine routine examination,liver and kidney function tests and chest X-ray examination were normal,and no pain or inflammation or loss of vision happened.4.The evaluation of the efficacy: Morphology: after UC-MSC SII,there was no significant difference of the fundus photography and FFA pre-treatment and post-treatment.OCT indicated the central foveal thickness and average macular thickness is stable(P>0.05),but the macular thickness of the one who diagnosed with macular edema pre-treatment obviously reduced in the third month,but went back in the 6 month.Function assessment: the best corrected visual acuity(BCVA)was better in 2,3,6 month post treatment(P<0.05),and performed the best in the third months;PVEP: P100 amplitude values,A / L ratio improved in the first month after UC-MSC SII,but the changes do not have any statistically significant.FVEP: P2 amplitude values,A/L ratio slightly decreased after treatment,and there is not statistically significant;the field of view and the visual field sensitivity displayed an increasing trend after treatment,but there is not statistically significant.NEI VFQ-25 scale scores increased post-treatment,and the score difference was statistically significant(P<0.05)in 3 month;Procalcitonin of all the patients were normal.Conclusion 1.There is no conclusive evidence for the UC-MSC directional homing to retina after the UC-MSC SII.However,in this study,the trial has been proved to be effect of neurotrophic and anti-inflammatory,and it could delay retinal neurons destruction in RCS rats.2.This study confirmed the security and efficacy of UC-MSC SII for advanced RP,and it could delay the progression of RP.The peak of effect of this novel approach is at 3 months after the SII. |
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