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Management of Retinitis Pigmentosa Via Combination of Wharton's Jelly-derived Mesenchymal Stem Cells and Magnovision

Primary Purpose

Retinitis Pigmentosa

Status
Completed
Phase
Phase 3
Locations
Turkey
Study Type
Interventional
Intervention
Wharton's jelly derived mesenchymal stemcells
Magnovision
Sponsored by
Ankara Universitesi Teknokent
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Retinitis Pigmentosa focused on measuring Retinitis pigmentosa,, stemcell, Wharton jelly, umbilical cord, mesenchymal stemcell, electromagnetic stimulation, iontophoresis, Magnovision.

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • BioRetina
  • Ankara University Biotechnology Institute
  • Umut Arslan

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

No Intervention

Arm Label

Only WJ-MSCs

Only rEMS

WJ-MSCs and rEMS combination

The natural course

Arm Description

Consisted of 34 eyes of 32 RP patients treated with only WJ-MSCs, and it was applied only once following necessary preparations. After the inoculation of stem cells, the patients were followed up regularly on the 10th day, 3rd month, and every 6 months after that until 36 th months. For ethical reasons, the worse eye was selected to inject the stem cells instead of both eyes.

Consisted of 32 eyes of 16 RP patients treated with only rEMS. rEMS was applied with a custom-designed helmet once a week for 30 min for 36 months. Both eyes are stimulated at the same time with the specially designed system for ophthalmologic use (MagnoVisionTM).

Consisted of 32 eyes of 16 RP patients treated with the WJ-MSCs and rEMS combination. WJ-MSCs were applied first into the deep subtenon space of both eyes after necessary preparations. rEMS application was started 10 days after the WJ-MSC application with a custom-designed helmet for 30 min. WJ-MSCs were inoculated only once, and rEMS was applied regularly once a week for 30 min for 36 months. Both eyes are stimulated at the same time with the specially designed system for ophthalmologic use (MagnoVisionTM).

The natural course (control) group consisted of 32 eyes of 16 RP patients who received no treatment and were regularly followed until the 36th month. This group comprised patients who did not accept any treatment and/or were in good condition at baseline.

Outcomes

Primary Outcome Measures

Fundus autofluorescence surface area (FAF-field):
The pattern of FAF correlates well with functional tests such as perimetry and ERG. The ring of increased autofluorescence appears to represent the border between functional and dysfunctional retinas. Metabolically active photoreceptors/RPE appear as hyperfluorescent areas in the FAF device due to the presence of lipofuscin. The FAF device calculated the FAF field automatically after marking the horizontal and vertical longest axes of the hyperfluorescent field in the posterior pole.

Secondary Outcome Measures

ETDRS visual acuity (BCVA):
The visual acuity scores obtained from the T0 and T1 examinations were analyzed and compared using statistical tests to determine effectiveness.
Ellipsoid zone widths (EZW):
EZW showed healthy photoreceptors and was measured horizontally and vertically (HEZW and VEZW, respectively) on multimodal OCTA devices. A manual segmentation program was used for the measurement of EZW.
Fundus perimetry deviation index (FPDI):
FPDI records were examined in the 24/2 visual field (VF) of the computerized perimetry records. The FPDI offers data explaining how many of the 100 flashing points and what percentage of the visual field could be correctly seen by the patient. For VF analysis, practice rounds were carried out three times before the last assessments to avoid mistakes during the test.
Full-field multi-luminance flicker electroretinography magnitude (ERG-m):
Digital electroretinography is a non-invasive office-based objective test that measures the electrical activity of the global outer retinal cells in response to a light stimulus. ERG-m refers to the action potentials and phase deviations recorded from photoreceptors stimulated with different light intensities.

Full Information

First Posted
March 13, 2023
Last Updated
March 23, 2023
Sponsor
Ankara Universitesi Teknokent
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1. Study Identification

Unique Protocol Identification Number
NCT05800301
Brief Title
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

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
January 1, 2019 (Actual)
Primary Completion Date
December 31, 2021 (Actual)
Study Completion Date
December 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ankara Universitesi Teknokent

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinitis Pigmentosa
Keywords
Retinitis pigmentosa,, stemcell, Wharton jelly, umbilical cord, mesenchymal stemcell, electromagnetic stimulation, iontophoresis, Magnovision.

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Only WJ-MSCs
Arm Type
Active Comparator
Arm Description
Consisted of 34 eyes of 32 RP patients treated with only WJ-MSCs, and it was applied only once following necessary preparations. After the inoculation of stem cells, the patients were followed up regularly on the 10th day, 3rd month, and every 6 months after that until 36 th months. For ethical reasons, the worse eye was selected to inject the stem cells instead of both eyes.
Arm Title
Only rEMS
Arm Type
Active Comparator
Arm Description
Consisted of 32 eyes of 16 RP patients treated with only rEMS. rEMS was applied with a custom-designed helmet once a week for 30 min for 36 months. Both eyes are stimulated at the same time with the specially designed system for ophthalmologic use (MagnoVisionTM).
Arm Title
WJ-MSCs and rEMS combination
Arm Type
Active Comparator
Arm Description
Consisted of 32 eyes of 16 RP patients treated with the WJ-MSCs and rEMS combination. WJ-MSCs were applied first into the deep subtenon space of both eyes after necessary preparations. rEMS application was started 10 days after the WJ-MSC application with a custom-designed helmet for 30 min. WJ-MSCs were inoculated only once, and rEMS was applied regularly once a week for 30 min for 36 months. Both eyes are stimulated at the same time with the specially designed system for ophthalmologic use (MagnoVisionTM).
Arm Title
The natural course
Arm Type
No Intervention
Arm Description
The natural course (control) group consisted of 32 eyes of 16 RP patients who received no treatment and were regularly followed until the 36th month. This group comprised patients who did not accept any treatment and/or were in good condition at baseline.
Intervention Type
Biological
Intervention Name(s)
Wharton's jelly derived mesenchymal stemcells
Intervention Description
The WJ-MSCs suspension from the culture was delivered to the operating room by cold chain and used within 24 h. A total of 1.5 ml of the WJ-MSC suspension was immediately injected into the deep subtenon space of each eye.
Intervention Type
Device
Intervention Name(s)
Magnovision
Other Intervention Name(s)
Electromagnetic stimulator, iontophoresis, neuromodulator
Intervention Description
Specifically designed helmets producing high-frequency repetitive electromagnetic stimulation (MagnovisionTM, Bioretina Biotechnology, Ankara, Türkiye) stimulated the retinas and visual pathways in both eyes.
Primary Outcome Measure Information:
Title
Fundus autofluorescence surface area (FAF-field):
Description
The pattern of FAF correlates well with functional tests such as perimetry and ERG. The ring of increased autofluorescence appears to represent the border between functional and dysfunctional retinas. Metabolically active photoreceptors/RPE appear as hyperfluorescent areas in the FAF device due to the presence of lipofuscin. The FAF device calculated the FAF field automatically after marking the horizontal and vertical longest axes of the hyperfluorescent field in the posterior pole.
Time Frame
Change between the 36th month (Time1) and baseline (Time0) values.
Secondary Outcome Measure Information:
Title
ETDRS visual acuity (BCVA):
Description
The visual acuity scores obtained from the T0 and T1 examinations were analyzed and compared using statistical tests to determine effectiveness.
Time Frame
Change between the 36th month (Time1) and baseline (Time0) values.
Title
Ellipsoid zone widths (EZW):
Description
EZW showed healthy photoreceptors and was measured horizontally and vertically (HEZW and VEZW, respectively) on multimodal OCTA devices. A manual segmentation program was used for the measurement of EZW.
Time Frame
Change between the 36th month (Time1) and baseline (Time0) values.
Title
Fundus perimetry deviation index (FPDI):
Description
FPDI records were examined in the 24/2 visual field (VF) of the computerized perimetry records. The FPDI offers data explaining how many of the 100 flashing points and what percentage of the visual field could be correctly seen by the patient. For VF analysis, practice rounds were carried out three times before the last assessments to avoid mistakes during the test.
Time Frame
Change between the 36th month (Time1) and baseline (Time0) values.
Title
Full-field multi-luminance flicker electroretinography magnitude (ERG-m):
Description
Digital electroretinography is a non-invasive office-based objective test that measures the electrical activity of the global outer retinal cells in response to a light stimulus. ERG-m refers to the action potentials and phase deviations recorded from photoreceptors stimulated with different light intensities.
Time Frame
Change between the 36th month (Time1) and baseline (Time0) values.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
BioRetina
City
Ankara
State/Province
Gölbaşı
ZIP/Postal Code
06570
Country
Turkey
Facility Name
Ankara University Biotechnology Institute
City
Ankara
State/Province
Türkiye
ZIP/Postal Code
06312
Country
Turkey
Facility Name
Umut Arslan
City
Ankara
ZIP/Postal Code
06000
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31385285
Citation
Ozmert E, Arslan U. Management of Deep Retinal Capillary Ischemia by Electromagnetic Stimulation and Platelet-Rich Plasma: Preliminary Clinical Results. Adv Ther. 2019 Sep;36(9):2273-2286. doi: 10.1007/s12325-019-01040-2. Epub 2019 Aug 5.
Results Reference
background
PubMed Identifier
33107400
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.
Results Reference
background
PubMed Identifier
31931872
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.
Results Reference
result
PubMed Identifier
32787913
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.
Results Reference
result
PubMed Identifier
34579767
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.
Results Reference
result
PubMed Identifier
32303913
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.
Results Reference
result

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Management of Retinitis Pigmentosa Via Combination of Wharton's Jelly-derived Mesenchymal Stem Cells and Magnovision

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