lipidunet-machine-learning-based-method-characterization

LipidUNet-Machine Learning-Based Method of Characterization and Quantification of Lipid Deposits Using iPSC-Derived Retinal Pigment Epithelium

The retinal pigment epithelium (RPE) is a monolayer of hexagonal cells located at the back of the eye. It provides nourishment and support to ...

National Institutes of Health (NIH)

Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have hindered disease treatments. Here, we show that ABCA4 knockout and induced pluripotent stem cell-derived RPE (STGD1-iRPE) from patients with Stargardt differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity-indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are lowered by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells.

Cell-replacement therapies are a new class of treatments, which include induced pluripotent stem cell (iPSC)-derived tissues that aim to replace degenerated cells. iPSCs can potentially be used to generate any cell type of the body, making them a powerful tool for treating degenerative diseases. Cell replacement for retinal degenerative diseases is at the forefront of cell therapies, given the accessibility of the eye for surgical procedures and a huge unmet medical need for retinal degenerative diseases with no current treatment options. Clinical trials are ongoing in different parts of the world using stem cell-derived retinal pigment epithelium (RPE). This review focuses on scientific and regulatory considerations when developing an iPSC-derived RPE cell therapy from the development of a robust and efficient differentiation protocol to critical quality control assays for cell validation, the choice of an appropriate animal model for preclinical testing, and the regulatory aspects that dictate the final approval for proceeding to a first-in-human clinical trial.

Mitra Farnoodian

Ocular and Stem Cell Translational Research Section,
National Eye Institute,
Ocular and Stem Cell Translational Research Section, National Eye Institute

National Institutes of Health (NIH)

LipidUNet-Machine Learning-Based Method of Characterization and Quantification of Lipid Deposits Using iPSC-Derived Retinal Pigment Epithelium

Mitra Farnoodian

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Ocular and Stem Cell Translational Research Section,National Eye Institute,Ocular and Stem Cell Translational Research Section, National Eye Institute

National Institutes of Health (NIH)

LipidUNet-Machine Learning-Based Method of Characterization and Quantification of Lipid Deposits Using iPSC-Derived Retinal Pigment Epithelium

Ocular and Stem Cell Translational Research Section,
National Eye Institute,
Ocular and Stem Cell Translational Research Section, National Eye Institute