Modeling Ocular Developmental Diseases From 3D Cultures of Optic Vesicle Organoids Derived From hiPSCs of Patients With Ocular Malformations (OrganoEye)

Ocular morphogenesis is a complex process starting as early as the 4th week of embryonic life, involving interactions between varioustissues of different origin and conserved genes. Anomalies in ocular development , often of genetic origin, pose diagnostic and therapeutic challenges. Animal models are limited, so human-induced pluripotent stem cell (hiPSC)-derived optic vesicle containing brain organoids (OVBOs) offer a promising alternative. These pathological OVBOs, created from patients' cells with ocular malformations, allow for the study of underlying molecular mechanisms and testing of therapies.

Study Overview

• Status: Not yet recruiting
• Conditions: Eye Abnormalities
• Intervention / Treatment: Biological: Blood sampling

Detailed Description

The eye's ability to perform its visual functions depends on its three-dimensional structure. Ocular morphogenesis is a complex process that begins in humans as early as the 4th week of embryonic life, requiring coordinated interactions between various embryologically diverse tissues involving highly conserved genes (Cardozo MJ, 2023). Disruption in any of these stages of ocular development, due to genetic, toxic, or environmental factors, can result in growth or formation defects of the eye globe. Among the most frequent ocular developmental anomalies , there are micro-anophthalmia, coloboma, anterior segment dysgenesis and aniridia (Plaisancie J, 2019). Most of these anomalies are of genetic origin. The primary obstacle in understanding these diseases is the lack of easily accessible tissue for sampling, which would allow for expression analyses and the study of underlying molecular mechanisms.

In this group of pathologies, understanding the pathophysiological mechanisms and therapeutic development was until recently quite limited and relied almost exclusively on the establishment of genetically modified animal models, a procedure that is lengthy, costly, and cumbersome. Moreover, routine diagnostic use of this model is not feasible in a hospital setting. Therefore, it is necessary to develop new tools and models to advance the understanding and management of these pathologies. The use of human induced pluripotent stem cells (hiPSCs) now allows for the understanding of the complexity of early organ development through the generation of 3D cellular models. Indeed, recent studies have shown that hiPSC-derived brain organoids retain, in a specific culture environment, the intrinsic capacity to develop optic vesicles (OV) mimicking early physiological ocular development and containing various ocular tissues (Gabriel E, 2021).

The optic vesicle organoid (OVBO) model thus represents a preferred alternative to the animal model in studying pathophysiological mechanisms and their use in preclinical trials. In addition to ethical and financial considerations, the latter has numerous advantages, particularly allowing the study of defective mechanisms directly from patient cells (precision medicine). Researchers have already developed the OVBO model from control hiPSC lines and have characterized the model under "physiological" conditions.

The next step in understanding the model and proving its utility in patients relies on studying the induced phenotype in OVBO models generated from hiPSCs from patients with genetically characterized ocular malformations. These "pathological" OVBO models will allow for detailed study of the molecular and cellular bases involved in these patients. Once the relevance of the model is demonstrated in modeling developmental pathologies of the eye, researchers will attempt to show that the OVBO model constitutes a robust alternative to the murine model in preclinical trials.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Julie Plaisancie, MD, PhD; Phone Number: +33 0561779075; Email: plaisancie.j@chu-toulouse.fr

Study Locations

• France
  • Toulouse, France, 31059
    • Purpan University Hospital
    • Contact: Julie Plaisancie, MD, PhD; Phone Number: +33 0561779075; Email: plaisancie.j@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

These patients will be solicited/sampled based on the genetic origin of the malformation they carry.

Description

Inclusion Criteria:

• Affiliated with a social security scheme.
• Patients with ocular malformations.
• Signed informed consent obtained from the patient and/or their legal representatives.

Exclusion Criteria:

• Inability to understand the nature and objectives of the study and/or difficulties in communicating with the investigator.
• Deprivation of liberty by judicial or administrative decision.
• Any other pathological or psychological condition deemed incompatible by the investigator for the proper conduct of the study.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Subjects presenting with an ocular developmental anomaly; Biological samples will be collected in the normal diagnosis and follow-up process	Biological: Blood sampling; Blood will be taken in larger quantity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Culture of Optic Vesicles containing Brain Organoids (OVBOs) for the Study of Eye malformations	Macroscopic Examination and Expression of Specific Tissue Markers to Identify Optic Vesicle Anomalies	Day 60 of Development

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular and Cellular Study of Genetically Characterized Ocular Malformations in Patients	Identification of Genetic Basis for Observed Patient Pathology	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Julie Plaisancie, MD, PhD, University Hospital, Toulouse

Study record dates

Study Major Dates

• Study Start (Estimated): May 2, 2024
• Primary Completion (Estimated): May 2, 2034
• Study Completion (Estimated): May 2, 2034

Study Registration Dates

• First Submitted: May 7, 2024
• First Submitted That Met QC Criteria: May 7, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Coloboma; Microphthalmia; Aniridia; Anophthalmia
• Additional Relevant MeSH Terms: Eye Diseases; Congenital Abnormalities; Eye Abnormalities
• Other Study ID Numbers: RC31/23/0626

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No