Safety and Efficacy of Stem Cell Small Extracellular Vesicles in Patients With Retinitis Pigmentosa

Официальное название

Safety and Efficacy Evaluation of Intravitreal Injection of GMP-compliant Bone Marrow Mesenchymal Stem Cell-derived Small Extracellular Vesicles in Patients With Retinitis Pigmentosa

Обзор

The aim of this clinical trials is to evaluate the safety and efficacy of intravitreal injection of GMP-compliant BM-MSC-derived sEVs in patients with retinitis pigmentosa.

Подробное описание

Inherited retinal disease (IRD) is one of the leading causes of blindness in adolescents and adults, affecting 1 in 2,000 to 3,000 people globally. Recently, advances arose in the use of stem cells as treatment modalities for inherited retinal diseases, including retinitis pigmentosa (RP).

The first step, production and characterization of GMP-compliant bone marrow mesenchymal stem cell (BM-MSC)-derived small extracellular vesicles (sEVs) has been performed according to the ethical clearance by the institutional review board of the Faculty of Medicine Siriraj Hospital Mahidol University (approval number Certificate of Approval (COA) no. Si 57112022, protocol number 44312565 (1RB1), dated August 8, 2022). In a prior study, the investigators have conducted a phase I clinical trial to assess the safety of intravitreal autologous MSC injection in 14 patients with advanced-stage RP. After follow-up periods ranging from 1.5 to 7 years, the investigators found that this intervention appeared to be safe and potentially effective. Nevertheless, several mild and one severe adverse event were observed, although all were manageable. Beside the primary outcome, safety of the MSCs, the investigators found statistically significant improvements in the best corrected visual acuity (BCVA) compared to baseline, although they returned to the baseline at 12 months. To minimize the unwanted effects and still maintain the benefit of the MSCs, the cell-free approach using the extracellular vesicles of MSCs is of interest.

On the current study, the investigators would like to evaluate the safety and efficacy of intravitreal injection of GMP-compliant BM-MSC-derived sEVs in patients with retinitis pigmentosa.

Вмешательства

• Биопрепарат GMP compliant-BM-MSC derived sEVs
  The procedure will be performed under topical anesthesia (0.5% tetracaine hydrochloride ophthalmic solution). The intravitreal injection will be performed by the retina specialist. Topical antiseptic (5% povidone iodine solution) will be applied on the periorbital and ocular surface. Eyelid speculum will be inserted to expose the injection area. It will include an intravitreal injection at the superotemporal quadrant (right eye) and superonasal quadrant (left eye), 3.5 to 4 mm posterior to the l

Первичные конечные точки

• Incidence of treatment-emergent adverse events [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]
• Ophthalmological parameters [Срок оценки: 1 year]

Критерии участия

Критерии включения

• Age 18 years or above
• Clinically diagnosed with RP by experienced ophthalmologists or having documented mutations in the genes responsible for RP
• Central visual field in the better eye less than or equal to 20 degrees
• Best corrected visual acuity (BCVA) in the worse eye 6/18 (logMAR 0.48) to 6/120 (logMAR 1.3) by Snellen visual acuity chart
• Electroretinogram in the worse eye nonrecordable or the amplitudes were less than 25% of normal
• Willing and able to give informed consent for participation in the study

Критерии исключения

• Intolerance and/or contraindication to local anesthesia and other substances used during the procedure
• Pregnant or lactating woman
• Having blood-borne infections, i.e. Human immunodeficiency virus (HIV), hepatitis B or C, Human T-lymphotropic viruses (HTLV)
• Having any other significant ocular or non-ocular disease/disorder which may either put the subjects at risk because of participation in the study, or may influence the results of the study, or the subjects ability to participate in the study. This includes

• Inherited or acquired bleeding disorders, including the use of anticoagulant medications that cannot be stopped prior the procedure
• Autoimmune diseases, i.e., systemic lupus erythematosus, multiple sclerosis, fibromyalgia, Guillain-Barre syndrome
• Severe/uncontrolled chronic/metabolic diseases, e.g., diabetes mellitus, cardiovascular disease, chronic kidney disease, transient ischemic attack (TIA)/stroke
• Unable to complete the full course of the study or failed to return for follow up

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Таиланд · 1 центр

• Siriraj Hospital — Bangkok Noi

Публикации

• Cremers FPM, Boon CJF, Bujakowska K, Zeitz C. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype-Phenotype Correlations, and Inheritance Models. Genes (Basel). 2018 Apr 16;9(4):215. doi: 10.3390/genes9040215. PMID 29659558
• Duncan JL, Pierce EA, Laster AM, Daiger SP, Birch DG, Ash JD, Iannaccone A, Flannery JG, Sahel JA, Zack DJ, Zarbin MA; and the Foundation Fighting Blindness Scientific Advisory Board. Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps. Transl Vis Sci Technol. 2018 Jul 18;7(4):6. doi: 10.1167/tvst.7.4.6. eCollection 2018 Jul. No abstract available. PMID 30034950
• Rodrigues GA, Shalaev E, Karami TK, Cunningham J, Slater NKH, Rivers HM. Pharmaceutical Development of AAV-Based Gene Therapy Products for the Eye. Pharm Res. 2018 Dec 27;36(2):29. doi: 10.1007/s11095-018-2554-7. PMID 30591984
• Lipinski DM, Thake M, MacLaren RE. Clinical applications of retinal gene therapy. Prog Retin Eye Res. 2013 Jan;32:22-47. doi: 10.1016/j.preteyeres.2012.09.001. Epub 2012 Sep 17. PMID 22995954
• Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, Hoyng CB, Roepman R, Klevering BJ. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018 Sep;66:157-186. doi: 10.1016/j.preteyeres.2018.03.005. Epub 2018 Mar 27. PMID 29597005
• Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007 Nov 15;110(10):3499-506. doi: 10.1182/blood-2007-02-069716. Epub 2007 Jul 30. PMID 17664353
• Salehi H, Amirpour N, Razavi S, Esfandiari E, Zavar R. Overview of retinal differentiation potential of mesenchymal stem cells: A promising approach for retinal cell therapy. Ann Anat. 2017 Mar;210:52-63. doi: 10.1016/j.aanat.2016.11.010. Epub 2016 Dec 13. PMID 27986614
• Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy. World J Stem Cells. 2019 Nov 26;11(11):957-967. doi: 10.4252/wjsc.v11.i11.957. PMID 31768222

Идентификаторы

NCT: NCT06242379 · R016534006

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗