Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton's Jelly Derived Mesenchymal Stem Cells (WJ-MSC)

Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton's Jelly Derived Mesenchymal Stem Cells

Management of Retinitis Pigmentosa by Wharton's Jelly Derived Mesenchymal Stem Cells: Preliminary Clinical Results

The aim of this study is to determine if umbilical cord Wharton's jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in retinitis pigmentosa patients by reactivating the degenerated photoreceptors in dormant phase.

The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier between photoreceptor cells and choroidal blood vessels. Photoreceptor cells are vitally and functionally dependent on the RPE. The conversion of blood glucose to ATP, synthesis of proteins in the visual cycle and removal of metabolic waste takes place in the RPE. For these important processes, various peptide growth factors and their receptors are synthesized in the RPE. More than 260 genes in the RPE are responsible for the production of these peptide fragments. Mutations in any of these genes as well as ischemic, physical or chemical RPE damage causes retinal degeneration. Retinal degeneration may be inherited, such as in retinitis pigmentosa (RP), Stargardt's disease, choroideremia, Best vitelliform dystrophy and Bietti's crystalline dystrophy. Retinal degeneration may also be acquired through genetic mechanisms, such as age-releated macular degeneration. In retinal degeneration, there is a developing loss of RPE and photoreceptors, regardless of the underlying cause. Umbilical cord Wharton's jelly derived mesenchymal stem cells (WJ-MSCs) have significant paracrine and immunomodulatory properties. WJ-MSCs secrete trophic factors that stimulate RPE or secrete trophic factors that are similar to those produced by RPE. In studies using animal models, WJ-MSCs have been found to be effective in stopping the progression of retinal degeneration and for rescuing photoreceptors in the dormant phase. WJ-MSCs are hypoimmunogenic and have significant immunomodulatory properties. WJ-MSCs have been shown to suppress chronic inflammation and prevent apoptosis in animal models of neurodegenerative and ischemic retinal disorders. WJ-MSCs also stimulate progenitor cells in the retina and elicit self-repair mechanisms. The aim of this preliminary clinical study is to investigate the efficacy of deep sub-tenon injected WJ-MSCs as a stem cell treatment modality for the management of retinitis pigmentosa, which creates outer retinal degeneration. These functional and structural effects were investigated using microperimetry, electrophysiology and spectral domain optical coherence tomography (SD-OCT). To the best of our knowledge, this is the first prospective clinical study that utilizes a large number of RP cases, and cases that are in phase-3.

Prospective, open-label clinical trial; The statistical comparisons were made primarily between the baseline and final values from the same eye. The parametric results for visual functions and structural changes were analyzed.

The mesenchymal cells that were used in this study were isolated from Wharton's jelly of the umbilical cord that was collected allogenicly from a single donor with the mother's consent. All cell preparation and cultivation procedures were conducted in a current Good Manufacturing Practice (cGMP) accredited laboratory (Onkim Stem Cell Technologies, Turkey).Cells were solubilized from cryopreservation before being made ready for injection. Average cell viability for each treatment was over 90.0% and each patient received cell numbers between 2-6x106 in a 1.5 ml saline solution .

The visual acuity scores obtained from the baseline testing and the final examination were analyzed and compared statistically to determine effectiveness.

This is the thickness from the outer plexiform layer to the Bruch membrane in the 3x3 mm area of the fovea measured (and recorded automatically) by the multimodal imaging OCTA device.

Inclusion Criteria: • 18 years of age or older; Diagnosis of any phenotypic or genotypic variation of RP, confirmed by clinical history, fundus appearance, visual field (VF), electroretinogram (ERG) and genetic mutation analysis; Having experienced various degrees of VF loss; BCVA from 50 letters to 110 letters in the ETDRS chart testing (Topcon CC-100 XP, Japan); Mean deviation (MD) values ranging between -33.0 and -5.0 dB with Compass visual field analysis (threshold 24-2, Sita Standard, Stimulus 3-white); Intraocular pressure (IOP) of <22 mmHg. Exclusion Criteria: • The presence of cataracts or other media opacity that might affect the VF, MD, or ERG recordings; The presence of glaucoma, which causes visual field and optic disc changes; The presence of any systemic disorder (e.g.,diabetes, neurological disease, or uncontrolled systemic hypertension) that may affect visual function; The habit of smoking.

Musial-Wysocka A, Kot M, Sulkowski M, Badyra B, Majka M. Molecular and Functional Verification of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) Pluripotency. Int J Mol Sci. 2019 Apr 12;20(8):1807. doi: 10.3390/ijms20081807.

Leow SN, Luu CD, Hairul Nizam MH, Mok PL, Ruhaslizan R, Wong HS, Wan Abdul Halim WH, Ng MH, Ruszymah BH, Chowdhury SR, Bastion ML, Then KY. Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration. PLoS One. 2015 Jun 24;10(6):e0128973. doi: 10.1371/journal.pone.0128973. eCollection 2015.

Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications. Mol Ther. 2015 May;23(5):812-823. doi: 10.1038/mt.2015.44. Epub 2015 Mar 19.

Canto-Soler V, Flores-Bellver M, Vergara MN. Stem Cell Sources and Their Potential for the Treatment of Retinal Degenerations. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(5):ORSFd1-9. doi: 10.1167/iovs.16-19127.

Garg A, Yang J, Lee W, Tsang SH. Stem Cell Therapies in Retinal Disorders. Cells. 2017 Feb 2;6(1):4. doi: 10.3390/cells6010004.

Mohamed EM, Abdelrahman SA, Hussein S, Shalaby SM, Mosaad H, Awad AM. Effect of human umbilical cord blood mesenchymal stem cells administered by intravenous or intravitreal routes on cryo-induced retinal injury. IUBMB Life. 2017 Mar;69(3):188-201. doi: 10.1002/iub.1608. Epub 2017 Feb 5.

Limoli PG, Vingolo EM, Limoli C, Scalinci SZ, Nebbioso M. Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report. J Vis Exp. 2018 Feb 12;(132):56469. doi: 10.3791/56469.

Ozmert E, Arslan U. Management of retinitis pigmentosa by Wharton's jelly-derived mesenchymal stem cells: prospective analysis of 1-year results. Stem Cell Res Ther. 2020 Aug 12;11(1):353. doi: 10.1186/s13287-020-01870-w.