Exploratory Analysis of ELP1 Expression in Whole Blood From Patients With Familial Dysautonomia

Background Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue‐specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood‐based ELP‐1 protein assay may provide a reliable way to monitor gene target engagement. Design and Methods Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. Results ELP1 protein levels were significantly lower in FD patients compared to heterozygous carriers (244 ± 75 vs. 2210 ± 1031 pg/mL, p < 0.001). Replicate analysis of 43 paired samples showed strong consistency in ELP1 levels ( p < 0.000). Repeat measurements 1 year after baseline showed longitudinal stability ( R 2 = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%–99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non‐affected carriers. Conclusion Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene‐targeted therapies aimed at correcting ELP1 gene splicing and protein production.