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

Retinitis Pigmentosa Clinical Trial

Official title:

Bioretina, Ankara University Technopolis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05800301
• Other study ID #: 11-962-19
• Status: Completed
• Phase: Phase 3
• Start date: January 1, 2019
• Est. completion date: December 31, 2022

Study information

• Verified date: March 2023
• Source: Ankara Universitesi Teknokent
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: December 31, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Retinitis
• Retinitis Pigmentosa

Intervention

Biological:
• Wharton's jelly derived mesenchymal stemcells
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.

Device:
• Magnovision
Specifically designed helmets producing high-frequency repetitive electromagnetic stimulation (MagnovisionTM, Bioretina Biotechnology, Ankara, Türkiye) stimulated the retinas and visual pathways in both eyes.

Locations

Country	Name	City	State
Turkey	Ankara University Biotechnology Institute	Ankara	Türkiye
Turkey	BioRetina	Ankara	Gölbasi
Turkey	Umut Arslan	Ankara

Sponsors (1)

Lead Sponsor	Collaborator
Ankara Universitesi Teknokent

Country where clinical trial is conducted

Turkey, 

References & Publications (6)

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 1 — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Change between the 36th month (Time1) and baseline (Time0) values.
Secondary	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.	Change between the 36th month (Time1) and baseline (Time0) values.
Secondary	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.	Change between the 36th month (Time1) and baseline (Time0) values.
Secondary	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.	Change between the 36th month (Time1) and baseline (Time0) values.
Secondary	Full-?eld 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.	Change between the 36th month (Time1) and baseline (Time0) values.