MSC-Exos Promote Healing of MHs

Macular Holes Clinical Trial

— MSCs  

Official title:

Mesenchymal Stem Cells Derived Exosomes Promote Healing of Large and Refractory Macular Holes

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03437759
• Other study ID #: 2015KY-05
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: March 1, 2017
• Est. completion date: December 30, 2021

Study information

• Verified date: April 2021
• Source: Tianjin Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Purpose: To assess the safety and efficacy of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) for promoting healing of large and refractory macular holes (MHs). Hypothesis: MSC and MSC-Exo therapy may promote functional and anatomic recovery from MH. MSC-Exo therapy may be a useful and safe method for improving visual outcomes of surgery for refractory MHs.

Description:

Based on the purpose and hypothesis,the participants with large and longstanding idiopathic MHs underwent vitrectomy, internal limiting membrane peeling, MSC or MSC-Exo intravitreal injection, and heavy silicon oil, air, 20% SF6, or 14% C3F8 tamponade. MSCs were isolated from human umbilical cord, and MSC-Exos were isolated from supernatants of MSCs via sequential ultracentrifugation. At the time of study enrollment, as well as physical examinations, best-corrected visual acuity (BCVA) and intraocular pressure will be measured and fundoscopy be performed. All diagnoses of MH are going to confirmed via spectral-domain optical coherence tomography (OCT), and the minimum linear diameter (MLD) of each MH will be measured parallel to the retinal pigment epithelium.The participants are going to be followed up for at least 6 months via BCVA measurement, fundoscopy, OCT, and physical examinations.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 44
• Est. completion date: December 30, 2021
• Est. primary completion date: May 30, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 80 Years

Eligibility

Inclusion Criteria:

1.Clinical diagnosis of idiopathic macular hole whose diameter is greater than 400 microns

Exclusion Criteria:

1. Only one functional eye

2. In other clinical trials.

3. Other diseases which can affect visual acuity, such as cataract, diabetic retinopathy, glaucoma, corneal diseases, etc.

4. Eye had undergone vitrectomy or scleral buckling, cataract surgery, Nd:YAG laser less than one month ago.

5. Contralateral eye has poor prognosis than the study eye.

6. Idiopathic or autoimmune uveitis history.

7. Aphakic eye

8. Physical condition is poor that can not keep prone position.

9. Secondary macular lesions

10. The equivalent spherical diopter of the study eye before any refractive correction or cataract surgery, which is greater than 6.0d or above 26mm of the ocular axis of the study eye.

11. Intraocular pressure is higher than 25mmHg

12. Within ocular inflammation, such as eye blepharitis, scleritis, keratitis and conjunctivitis.

13. Systemic condition is poor, such as the poor control of diabetes and hypertension, myocardial infarction, cerebrovascular accident, renal failure and so on,and the researchers assessed those who are unable to complete the trail.

Related Conditions & MeSH terms

• Macular Holes
• Retinal Perforations

Intervention

Biological:
• exosomes derived from mesenchymal stem cells (MSC-Exo)
After air-liquid exchange, 50µg or 20µg MSC-Exo in 10µl PBS was dripped into vitreous cavity around MH, leaving 20% SF6 or air as tamponade .

Locations

Country	Name	City	State
China	Tianjin Medical University Hospital	Tianjin

Sponsors (1)

Lead Sponsor	Collaborator
Tianjin Medical University

Country where clinical trial is conducted

China, 

References & Publications (38)

Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, Yu B, Chen X, Li X, Zhang X. Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis. Sci Rep. 2017 Jun 28;7(1):4323. doi: 10.1038/s41598-017-04559-y. Erratum in: Sci Rep. 2018 Jun — View Citation

Chen X, Shao H, Zhi Y, Xiao Q, Su C, Dong L, Liu X, Li X, Zhang X. CD73 Pathway Contributes to the Immunosuppressive Ability of Mesenchymal Stem Cells in Intraocular Autoimmune Responses. Stem Cells Dev. 2016 Feb 15;25(4):337-46. doi: 10.1089/scd.2015.022 — View Citation

Cillino S, Cillino G, Ferraro LL, Casuccio A. TREATMENT OF PERSISTENTLY OPEN MACULAR HOLES WITH HEAVY SILICONE OIL (DENSIRON 68) VERSUS C2F6. A PROSPECTIVE RANDOMIZED STUDY. Retina. 2016 Apr;36(4):688-94. doi: 10.1097/IAE.0000000000000781. — View Citation

De Novelli FJ, Preti RC, Ribeiro Monteiro ML, Pelayes DE, Junqueira Nóbrega M, Takahashi WY. Autologous Internal Limiting Membrane Fragment Transplantation for Large, Chronic, and Refractory Macular Holes. Ophthalmic Res. 2015;55(1):45-52. doi: 10.1159/00 — View Citation

Del Priore LV, Kaplan HJ, Bonham RD. Laser photocoagulation and fluid-gas exchange for recurrent macular hole. Retina. 1994;14(4):381-2. — View Citation

Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl Med. 2015 Oct;4( — View Citation

Ezra E, Gregor ZJ; Morfields Macular Hole Study Ggroup Report No. 1. Surgery for idiopathic full-thickness macular hole: two-year results of a randomized clinical trial comparing natural history, vitrectomy, and vitrectomy plus autologous serum: Morfields — View Citation

Hillenkamp J, Kraus J, Framme C, Jackson TL, Roider J, Gabel VP, Sachs HG. Retreatment of full-thickness macular hole: predictive value of optical coherence tomography. Br J Ophthalmol. 2007 Nov;91(11):1445-9. Epub 2007 May 2. — View Citation

Jiang Y, Zhang Y, Zhang L, Wang M, Zhang X, Li X. Therapeutic effect of bone marrow mesenchymal stem cells on laser-induced retinal injury in mice. Int J Mol Sci. 2014 May 27;15(6):9372-85. doi: 10.3390/ijms15069372. — View Citation

Johnson RN, McDonald HR, Schatz H, Ai E. Outpatient postoperative fluid-gas exchange after early failed vitrectomy surgery for macular hole. Ophthalmology. 1997 Dec;104(12):2009-13. — View Citation

Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010 Nov;5(6):933-46. doi: 10.2217/rme.10.72. Review. — View Citation

Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013 Jul 10;335(1):201-4. doi: 10.1016/j.canlet.2013.02.019. Epub 2013 Feb 16 — View Citation

Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holes. Results of a pilot study. Arch Ophthalmol. 1991 May;109(5):654-9. — View Citation

Kim JY, Kwon OW. VITRECTOMY FOR REFRACTORY MACULAR HOLE. Retin Cases Brief Rep. 2015 Fall;9(4):265-8. doi: 10.1097/ICB.0000000000000183. — View Citation

Kozy DW, Maberley AL. Closure of persistent macular holes with human recombinant transforming growth factor-beta 2. Can J Ophthalmol. 1996 Jun;31(4):179-82. — View Citation

Li G, Yuan L, Ren X, Nian H, Zhang L, Han ZC, Li X, Zhang X. The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis. Clin Exp Immunol. 2013 Jul;173(1):28-37. doi: 10.1111/cei.12080. — View Citation

Liggett PE, Skolik DS, Horio B, Saito Y, Alfaro V, Mieler W. Human autologous serum for the treatment of full-thickness macular holes. A preliminary study. Ophthalmology. 1995 Jul;102(7):1071-6. — View Citation

Machalinska A, Kawa M, Pius-Sadowska E, Stepniewski J, Nowak W, Roginska D, Kaczynska K, Baumert B, Wiszniewska B, Józkowicz A, Dulak J, Machalinski B. Long-term neuroprotective effects of NT-4-engineered mesenchymal stem cells injected intravitreally in — View Citation

Maltman DJ, Hardy SA, Przyborski SA. Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem Int. 2011 Sep;59(3):347-56. doi: 10.1016/j.neuint.2011.06.008. Epub 2011 Jun 21. Review. — View Citation

Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010 Oct;117(10):2018-25. doi: 10.1016/j.ophtha.2010.02.011. Epub 2010 Jun 11. — View Citation

Michalewska Z, Michalewski J, Cisiecki S, Adelman R, Nawrocki J. Correlation between foveal structure and visual outcome following macular hole surgery: a spectral optical coherence tomography study. Graefes Arch Clin Exp Ophthalmol. 2008 Jun;246(6):823-3 — View Citation

Morizane Y, Shiraga F, Kimura S, Hosokawa M, Shiode Y, Kawata T, Hosogi M, Shirakata Y, Okanouchi T. Autologous transplantation of the internal limiting membrane for refractory macular holes. Am J Ophthalmol. 2014 Apr;157(4):861-869.e1. doi: 10.1016/j.ajo — View Citation

Ohana E, Blumenkranz MS. Treatment of reopened macular hole after vitrectomy by laser and outpatient fluid-gas exchange. Ophthalmology. 1998 Aug;105(8):1398-403. — View Citation

Pearson RA, Gonzalez-Cordero A, West EL, Ribeiro JR, Aghaizu N, Goh D, Sampson RD, Georgiadis A, Waldron PV, Duran Y, Naeem A, Kloc M, Cristante E, Kruczek K, Warre-Cornish K, Sowden JC, Smith AJ, Ali RR. Donor and host photoreceptors engage in material t — View Citation

Rahmani B, Tielsch JM, Katz J, Gottsch J, Quigley H, Javitt J, Sommer A. The cause-specific prevalence of visual impairment in an urban population. The Baltimore Eye Survey. Ophthalmology. 1996 Nov;103(11):1721-6. — View Citation

Rizzo S, Belting C, Genovesi-Ebert F, Cresti F, Vento A, Martini R. Successful treatment of persistent macular holes using "heavy silicone oil" as intraocular tamponade. Retina. 2006 Oct;26(8):905-8. — View Citation

Rotenstreich Y, Tzameret A, Kalish SE, Belkin M, Meir A, Treves AJ, Naglera A, Sher I. [A novel system for minimally invasive transplantation of bone marrow derived stem cells as a thin layer in the subretina and extravascular spaces of the choroid--for t — View Citation

Singh MS, Balmer J, Barnard AR, Aslam SA, Moralli D, Green CM, Barnea-Cramer A, Duncan I, MacLaren RE. Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion. Nat Commun. 2016 Nov 30;7:13537. do — View Citation

Suda K, Hangai M, Yoshimura N. Axial length and outcomes of macular hole surgery assessed by spectral-domain optical coherence tomography. Am J Ophthalmol. 2011 Jan;151(1):118-127.e1. doi: 10.1016/j.ajo.2010.07.007. — View Citation

Wells JA, Gregor ZJ. Surgical treatment of full-thickness macular holes using autologous serum. Eye (Lond). 1996;10 ( Pt 5):593-9. — View Citation

Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012 Jul;30(7):1556-64. doi: 1 — View Citation

Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014 Nov 10;8:377. doi: 10.3389/fncel.2014.00377. eCollection 2014. Review. — View Citation

Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particle — View Citation

Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013 Mar;65(3):336-41. doi: 10.1016/j.addr.2012.07.001. Epub 2012 Jul 7. Review. — View Citation

Yu B, Shao H, Su C, Jiang Y, Chen X, Bai L, Zhang Y, Li Q, Zhang X, Li X. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016 Sep 30;6:34562. doi: 10.1038/srep34562. — View Citation

Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014 Mar 7;15(3):4142-57. doi: 10.3390/ijms15034142. Review. — View Citation

Zhang L, Zheng H, Shao H, Nian H, Zhang Y, Bai L, Su C, Liu X, Dong L, Li X, Zhang X. Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental autoimmune uveitis of rats. Invest Ophthalmol Vis Sci. 2014 A — View Citation

Zhang X, Ren X, Li G, Jiao C, Zhang L, Zhao S, Wang J, Han ZC, Li X. Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity. Invest Ophthalmol Vis Sci. 2011 May 16;52(6):3143-52. doi: 1 — View Citation

* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Macular holes closure	Minimum linear diameter (MLD) of the hole measured by OCT	baseline to 24 weeks post-surgery
Secondary	Best corrected visual acuity(BCVA)	BCVA using a Landolt C acuity chart method	baseline to 24 weeks post-surgery