Insights and future directions for the application of perinatal derivatives in eye diseases: A critical review of preclinical and clinical studies

Abstract

Perinatal derivatives (PnD) are gaining interest as a source for cell-based therapies. Since the eye is easily accessible to local administration, eye diseases may be excellent candidates to evaluate novel therapeutic approaches. With this work, we performed a systematic review of published preclinical and clinical studies addressing PnD in the treatment of ocular diseases. We have set two specific objectives: (i) to investigate the current level of standardization in applied technical procedures in preclinical studies and (ii) to assess clinical efficacy in clinical trials. Hereto, we selected studies that applied amniotic membrane (hAM) and mesenchymal stromal cells derived from amniotic membrane (hAMSC), placenta (hPMSC), umbilical cord (hUC-MSC) and Wharton’s Jelly (hUC-WJ-MSC), excluding those where cells were not transplanted individually, following a systematic PubMed search for preclinical studies and consultation of clinical studies on https://clinicaltrials.gov and https://www.clinicaltrialsregister.eu/. Our bibliographic search retrieved 26 pre-clinical studies and 27 clinical trials. There was a considerable overlap regarding targeted ocular structures. Another common feature is the marked tendency towards (i) locally administered treatments and (ii) the PnD type. In the cornea/ocular surface, hAM was preferred and usually applied directly covering the ocular surface. For neuroretinal disorders, intra-ocular injection of umbilical or placental-derived cells was preferred. In general, basic research reported favourable outcomes. However, due to lack of standardization between different studies, until now there is no clear consensus regarding the fate of administered PnD or their mode of action. This might be accountable for the low index of clinical translation. Regarding clinical trials, only a minority provided results and a considerable proportion is in “unknown status”. Nevertheless, from the limited clinical evidence available, hAM proved beneficial in the symptomatic relief of bullous keratopathy, treating dry eye disease and preventing glaucoma drainage device tube exposure. Regarding neuroretinal diseases, application of Wharton’s Jelly MSC seems to become a promising future approach. In conclusion, PnD-based therapies seem to be beneficial in the treatment of several ocular diseases. However, much is yet to be done both in the pre-clinical and in the clinical setting before they can be included in the daily ophthalmic practice.

Guidelines to Analyze Preclinical Studies Using Perinatal Derivatives

“…From this extensive work of literature search and selection and data extraction, several systematic and comprehensive reviews are published already. These publications gathered and analyzed the existing literature on the application of preclinical studies on different fields, namely cutaneous wound healing [ 5 ], ovarian diseases [ 3 ], oncology [ 6 ], and ophthalmology [ 4 ]. All of these publications used the common search and data extraction strategy described here, with additional, disease-specific refinements as described in detail in the respective publications.…”

“…Another limitation to the future translation of preclinical results into clinical therapies is the lack of large animal models or the assessment of the in vivo biodistribution and the fate of applied PnD. As a consequence, the SPRINT consortium made recommendations on the reporting of PnD isolation and characterization, on the disease models with standardized time points for analysis and type of readouts and on the requirement to conduct in vitro functional tests to improve the reproducibility and power of preclinical studies [ 4 , 5 ].…”

“…The COST SPRINT Action (CA17116) published a consensus paper on the human placenta tissue and cell nomenclature [1]. The present protocol aims to: (1) serve as guidelines for the design and reporting of preclinical studies assessing the safety and therapeutic efficacy of PnD; (2) describe the SPRINT consortium's strategy for a comprehensive search and selection of the significant publications in the field; (3) outline the data extraction used to generate the SPRINT reviews for different therapeutic targets [3][4][5][6]; (4) foster the consensus on the proper study designs, and the knowledge of the therapeutic efficacy of PnD; (5) minimize redundancy in animal experimentation in line with the Replacement, Reduction, and Refinement (3R) principles for more ethical use of animals in research [7]. The focus of the SPRINT reviews of animal models for different diseases and injuries is set on assessing the studies for a clear definition of the research question in terms of population, interventions, comparators, outcomes, and study designs (PICOS) [8].…”

Recommendations from the COST action CA17116 (SPRINT) for the standardization of perinatal derivative preparation and in vitro testing

“…They presented standardized characterization of hAM and chorion and argue that this is critical for methods applicable to both in vitro and clinical studies ( Sabol et al, 2022 ). Norte-Muñoz et al (2022) , aimed to investigate the current level of standardization of applied technical procedures in preclinical studies using various PnDs. They argued that due to lack of standardization between the studies, which were selected following a systematic PubMed search, there is no clear consensus regarding the status of the administered PnD and their mode of action ( Norte-Muñoz et al, 2022 ).…”

“… Norte-Muñoz et al (2022) , aimed to investigate the current level of standardization of applied technical procedures in preclinical studies using various PnDs. They argued that due to lack of standardization between the studies, which were selected following a systematic PubMed search, there is no clear consensus regarding the status of the administered PnD and their mode of action ( Norte-Muñoz et al, 2022 ). In addition, Papait et al (2022) underline the lack of PnD potency assays and the need for their standardization.…”