Clinical trial NCT05800301: Management of Retinitis Pigmentosa Via Combination of Wharton's Jelly-derived Mesenchymal Stem Cells and Magnovision
Official title: Bioretina, Ankara University Technopolis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Retinitis Pigmentosa
Keywords: Retinitis pigmentosa,
stemcell
Wharton jelly
umbilical cord
mesenchymal stemcell
electromagnetic stimulation
iontophoresis
Magnovision.
Lead sponsor: Ankara Universitesi Teknokent
Sponsor class: OTHER
First posted: 2023-04-05
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A total of 130 eyes of 80 RP patients who could be checked regularly, mean 36 months of the follow-up period, were included in this study. Four different groups with similar demographic characteristics were created in the cohort
Primary purpose: SUPPORTIVE_CARE

Brief summary: Purpose To investigate whether the natural progression rate of retinitis pigmentosa (RP) can be decreased with subtenon umbilical cord Wharton's jelly derived mesenchymal stemcell (WJ-MSC) application alone or combination with retinal electromagnetic stimulation (rEMS).

Material and methods The study included prospective analysis of 130 eyes of 80 retinitis pigmentosa patients with a 36-month follow-up duration. Patients constitute 4 groups with similar demographic characteristics. The subtenon WJ-MSC only group consisted of 34 eyes of 32 RP patients as Group1; The rEMS only group consisted of 32 eyes of 16 RP patients as Group2; The combined management group consisted of 32 eyes of 16 RP patients who received combined WJ-MSC and rEMS as Group3; The natural course (control) group consisted of 32 eyes of 16 RP patients who did not receive any treatment were classified as Group4. Fundus autofluorescence surface area (FAF-field), horizontal and vertical ellipsoid zone width (EZW), fundus perimetry deviation index (FPDI), full field electroretinography magnitude (ERG-m) and best corrected visual acuity (BCVA) changes were compared within and between groups after 36 month follow up period.

Detailed description: Retinitis Pigmentosa (RP) is one of the most common inherited diseases of retinopathies. It is estimated to affect 1 in 3000 to 1 in 4000 people globally. Retinitis pigmentosa (RP) is a genetic disease group characterized by progressive loss of photoreceptors. At least 90 different structural and functional proteins have been identified in the sensory retina, which is necessary for the healthy functioning of the visual cycle. At least 300 genes encode these proteins, and their fragments have been identified in the sensory retina. Mutations in any of these 300 genes lead to outer retinal degeneration and RP. In classical RP, genetic mutations primarily impair the functions of rod cells. Structural and functional protein deficiency causes rod cells to enter the dormant phase and undergo apoptosis. The inheritance pattern can be autosomal dominant, autosomal recessive, X-linked, mitochondrial, or spontaneous mutations. The rate of disease progression is different in each inheritance pattern. Patients first complain of difficulty seeing at night and prolonged dark adaptation. As rod cell loss increases, the peripheral visual field begins to narrow. The narrowing of the visual field progresses at a rate of 5-15% each year, depending on the inheritance pattern, and finally, the cone cells are affected. Apoptosis of rod/cone cells results in end-stage RP, then progress to total blindness.

Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have a high paracrine effect and secrete exosomes containing different growth factors (GFs) and neurotrophins. These peptides in the exosome content are functional and structural peptides for neurons. Peptides that cannot be encoded in RP can be substituted by WJ-MSCs exosomes. Growth factors and neurotrophins in the exosome can accelerate the entry of glucose into retina pigment epithelium (RPE) and photoreceptors and their conversion to ATP, an energy molecule. These neurotrophins can also provide homeostasis, preventing apoptosis by accelerating the phagocytosis of cellular metabolic wastes.

High-frequency repetitive electromagnetic stimulation (rEMS) can modulate ion channels in neurons depending on frequency, magnetic field, and duration variables. If the dormant phase - which is the sleep mode caused by genetic mutations in the sensory retina - is prolonged, apoptosis and permanent photoreceptor loss occur. Activation of ion channels and acceleration of neuromodulation by electromagnetic stimulation can prevent neuronal apoptosis. Scientific studies have also shown that rEMS increases mesenchymal stem cells' exosome degranulation. Another effect of rEMS is the iontophoresis effect. The passage of large molecules into the cells through the scleral pores is possible by changing the electrical charges between neurotrophins and their receptors and increasing the affinity. It can also induce the delivery of higher amounts of GFs and neurotrophins into the subretinal environment and retina.

This prospective clinical study aims to investigate whether RP progression can be slowed or maintained with the inoculation of WJ-MSCs alone into the deep subtenon space or in conjunction with rEMS application compared to the natural course of the disease.

Eligibility criteria: Inclusion Criteria:

* RP patients of any genotype and phenotype;
* BCVA better than 35 letters;
* Any degree and kind of visual field loss;
* Over 18 years old.

Exclusion Criteria:

* The presence of glaucoma,
* Dense cataracts
* Dense vitreus opacities
* Autoimmune retinopathy-like clinical picture
* Any degree of smoking
* Presence of systemic neurological disease with seizure
* Presence of a cardiac pacemaker.

Primary outcomes:
measure: Fundus autofluorescence surface area (FAF-field):
timeFrame: Change between the 36th month (Time1) and baseline (Time0) values.
Secondary outcomes:
measure: ETDRS visual acuity (BCVA):
timeFrame: Change between the 36th month (Time1) and baseline (Time0) values.
measure: Ellipsoid zone widths (EZW):
timeFrame: Change between the 36th month (Time1) and baseline (Time0) values.
measure: Fundus perimetry deviation index (FPDI):
timeFrame: Change between the 36th month (Time1) and baseline (Time0) values.
measure: Full-ﬁeld multi-luminance flicker electroretinography magnitude (ERG-m):
timeFrame: Change between the 36th month (Time1) and baseline (Time0) values.
Other outcomes:
Locations:
city: Ankara
country: Turkey
facility: BioRetina
state: Gölbaşı
city: Ankara
country: Turkey
facility: Ankara University Biotechnology Institute
state: Türkiye
city: Ankara
country: Turkey
facility: Umut Arslan
Study officials:
References:
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citation: Arslan U, Ozmert E. Treatment of resistant chronic central serous chorioretinopathy via platelet-rich plasma with electromagnetic stimulation. Regen Med. 2020 Aug;15(8):2001-2014. doi: 10.2217/rme-2020-0056. Epub 2020 Oct 27.
citation: Ozmert E, Arslan U. Management of retinitis pigmentosa by Wharton's jelly derived mesenchymal stem cells: preliminary clinical results. Stem Cell Res Ther. 2020 Jan 13;11(1):25. doi: 10.1186/s13287-020-1549-6.
citation: 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.
citation: Ozmert E, Arslan U. Management of toxic optic neuropathy via a combination of Wharton's jelly-derived mesenchymal stem cells with electromagnetic stimulation. Stem Cell Res Ther. 2021 Sep 27;12(1):518. doi: 10.1186/s13287-021-02577-2.
citation: Arslan U, Ozmert E. Management of Retinitis Pigmentosa via Platelet-Rich Plasma or Combination with Electromagnetic Stimulation: Retrospective Analysis of 1-Year Results. Adv Ther. 2020 May;37(5):2390-2412. doi: 10.1007/s12325-020-01308-y. Epub 2020 Apr 18.