Researchers have created cell line models to better study the mechanisms of progressive chorioretinopathy in a form of long chain fatty acid oxidation disorder (LCFAOD). 

Tiffany DeVine, PhD
Credit: INFORM

Tiffany DeVine, PhD, postdoctoral researcher at the Gillingham lab at Oregon Health and Science University in Portland, presented data demonstrating that the Gillingham lab has been successful in creating a retinal pigment epithelium (RPE) model of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) from induced pluripotent stem cells (iPSCs).

The results were presented as part of the second day of the International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Conference hosted by Jerry Vockley, MD, PhD.

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Dr. DeVine and the rest of the lab created a number of different iPSC-RPE cell models, including LCHADD, to investigate possible mechanisms for the chorioretinopathy seen in patients.

The iPSC-RPE cells developed by the lab were found to be similar to RPE cells. They both have the ability to perform phagocytosis and clear outer segments from photoreceptors. The iPSC-RPE cells were also able to act as a blood-retinal barrier through the creation of tight junctions between cells, as evidenced by similar resistance levels to normal RPE cells.

Previous research into LFCAODs has shown that patients with trifunctional protein deficiency (TFPD) have more stable vision compared to LCHADD patients, who experienced a steady decline in visual acuity as they aged. A correlation between the accumulation of hydroxyacylcarnitines and vision loss was also observed previously.

“There is some evidence to suggest the 3-hydroxyacylcarnitines may cause oxidative stress, which could eventually lead to protein, DNA, and lipid damage. And then, over time, this could result in cell death,” Dr. DeVine said. “Another proposal is that since the fatty acids won’t complete the oxidation cycle that they are instead shunted to the peroxisome where they can be chain-shortened. And one of the products of this reaction is hydrogen peroxide (H2O2) which can also contribute to oxidative stress.”

Data from the lab showed that LCHADD iPSC-RPEs demonstrated reduced fat oxidation compared to wild type (WT) iPSC-RPEs, as seen through a lack of increase in oxygen consumption rates (OCR) and lower maximal respiration when the cells were exposed to palmitate.

Read more about LCFAOD complications

The LCHADD cells also were shown to release fewer ketones (P =.09) than WT cells. It is hypothesized that these ketone bodies are normally taken up and used by photoreceptors so a deficiency in their release may be harmful to the photoreceptors.

In addition, LCHADD RPE cells exhibited increased lipid accumulation (triglycerides) compared to WT cells. LCHADD RPE cells also caused increased levels of 3-hydroxyacylcarnitine in culture when given palmitate, compared with WT cells.

Long chain fatty acids were observed to decrease mitochondrial health in LCHADD RPE and these cells may be more susceptible to H2O2 induced oxidation damage that can be present in the retina. Dr. Devine hypothesized that this may be due to the presence of 3-hydroxyacylcarnitines comprising the defense system in LCHADD cells.

Patient cells (skin fibroblasts) were reprogrammed using the 4 Yamanaka factors to create induced pluripotent stem cells (iPSCs) that were later differentiated into RPE cells through a directed differentiation process. Cells were grown in a pigmented, hexagonal monolayer that showed the expression of RPE-specific proteins. The cells grow to confluence before becoming quiescent (nondividing) where they are able to survive for several months.

In the question-and-answer portion of the presentation, Dr. DeVine revealed that their lab actually has 3 LCHADD, 2 TFP, 2 wild type (WT), and 3 very long chain acyl-CoA dehydrogenase deficiency (VLCADD) cell lines stored as iPSCs that can be differentiated into RPE or other cells.


LCHAD deficiency in an iPSC-derived retinal pigment epithelium model. Presented at: International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Meeting: October 28, 2021; Virtual.