ELABELA

What is ELABELA?

ELABELA (also called Toddler or Apela) is a 32-amino-acid secreted peptide hormone identified in 2013–2014 as the second endogenous ligand of the APJ receptor (APLNR), the same G-protein-coupled receptor activated by apelin. It was independently discovered by two groups in the same year: Chng and colleagues at A*STAR (Singapore), who named it ELABELA based on its role in heart development, and Pauli and colleagues in the Schier lab, who named it Toddler based on the cell-movement phenotype of zebrafish loss-of-function mutants. ELABELA is critical in early embryogenesis — knockout animals develop with severe cardiovascular malformations or no heart at all. In adults, ELABELA expression narrows dramatically: it is most highly expressed in the kidney (collecting ducts and loops), with additional expression in prostate and placenta. Interest in ELABELA as a therapeutic has grown alongside evidence that it is downregulated in pulmonary arterial hypertension, pre-eclampsia, heart failure, and chronic kidney disease, and that exogenous administration reverses pathology in animal models. ELABELA is currently a research molecule — there is no approved product, no registered therapeutic clinical trial, and no established human dose.

What ELABELA Is Investigated For

ELABELA's research narrative has two chapters. The first is developmental: it is indispensable for embryonic heart and vascular formation, and this biology remains the clearest, most consistently replicated part of the story. The second is adult physiology and pathology, where the picture is still resolving. In animal models, exogenous ELABELA attenuates pulmonary arterial hypertension, rescues pre-eclampsia phenotypes in knockout dams, lowers blood pressure, protects against ischemia-reperfusion kidney injury, and reduces cardiac fibrosis and remodeling. Circulating ELABELA levels track inversely with severity in several human cardiovascular and renal conditions, positioning it as a candidate biomarker. What ELABELA is not: a validated therapeutic. Translational work — PEGylated analogues, APJ biased agonists, non-peptide mimetics — is active but early. No human therapeutic trials have been completed, and the handful of human observational studies that contradict the preclinical story (for example, finding no reduction in ELABELA in established pre-eclampsia) are a real signal that biology discovered in mice and zebrafish does not always map cleanly onto human disease.

History & Discovery

ELABELA has one of the most unusual discovery stories in recent peptide biology: two independent groups, working on different organisms with different questions, converged on the same molecule within months of each other in 2013–2014. The first paper, published in Developmental Cell in December 2013, came from Bruno Reversade's lab at A*STAR (Singapore), with Serene Chng as first author. They were profiling the secretome of human embryonic stem cells and noticed a small, highly conserved open reading frame that encoded a hormone-like peptide. They named it ELABELA — a phonetic riff meant to evoke a feminine, pretty word (like Isabella) reflecting its discovery in stem cells — and showed that zebrafish embryos lacking ela developed with rudimentary hearts or no heart at all, a phenotype identical to loss of the apelin receptor. The second paper, published in Science in February 2014, came from Alexander Schier's lab (then at Harvard), with Andrea Pauli as first author. The Schier group was running an unbiased screen for novel secreted signaling peptides in zebrafish and flagged the same short ORF. They named the peptide Toddler because zebrafish mutants moved their cells too slowly during gastrulation — as if toddling — and showed that Toddler acts as a motogen driving mesendodermal cell migration via APJ. Apela, the gene symbol, is a later harmonization (Apelin Early Endogenous Ligand). The adult-physiology chapter opened with the 2017 Science paper from Lena Ho and Reversade showing that ELABELA-knockout pregnant mice develop a preeclampsia-like syndrome rescued by exogenous ELABELA infusion — a result that attracted real translational interest. Work on ELABELA in pulmonary hypertension, kidney injury, and heart failure has grown steadily since, with stabilized analogues (PEGylated, lipid-acylated) and APJ biased agonists in preclinical development. No ELABELA-based therapeutic has yet entered late-stage clinical trials.

How It Works

ELABELA is a hormone that activates the same cellular receptor (APJ) that apelin binds to. It was discovered in 2013–2014 when two research groups — working independently, one studying zebrafish heart development and one studying cell movement in early embryos — found that the same peptide was essential for embryos to form a working heart. In adults, ELABELA is made mostly by the kidney, prostate, and placenta, and animal studies suggest it protects against high blood pressure in the lungs, complications of pregnancy, kidney injury, and heart failure. No ELABELA drug exists yet — it is still a research molecule.

ELABELA is encoded by the APELA gene and produced as a 54-amino-acid preprohormone; the mature, biologically active form is a 32-amino-acid peptide (ELABELA-32), with shorter processed isoforms (ELA-21, ELA-11) also identified. It binds and activates the apelin receptor (APJ / APLNR), a class A GPCR that couples primarily to Gαi/o and β-arrestin pathways. Compared to apelin, ELABELA shows biased signaling at APJ — ELABELA-32 in particular is strongly β-arrestin-biased, whereas shorter ELABELA and apelin isoforms differ in the strength of G-protein versus β-arrestin recruitment. Downstream effects include PI3K/AKT activation (important for hESC self-renewal and cardiomyocyte survival), inhibition of the intrarenal renin-angiotensin system, suppression of NADPH oxidase / ROS / NLRP3 inflammasome activation, and anti-fibrotic effects mediated in part through the IL-6/STAT3/GPX4 axis in hypertensive heart models. Developmentally, ELABELA drives mesendoderm migration during gastrulation (via APJ on migrating cells) and is required for cardiac progenitor specification and placental trophoblast differentiation. In adults, ELABELA is most abundantly expressed in renal collecting ducts and loops, consistent with its proposed role in fluid and sodium homeostasis. The peptide's native half-life is short, which has motivated development of PEGylated and lipid-acylated analogues with enhanced receptor binding and stability.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about ELABELA:

• 01Whether the striking mouse-knockout pre-eclampsia phenotype translates to human disease. Early human observational studies give mixed results, and the placenta does not appear to be the dominant source of circulating ELABELA in human pregnancy.
• 02What the optimal signaling bias at APJ is for different indications. ELABELA-32 is strongly β-arrestin-biased, but whether G-protein-biased or β-arrestin-biased agonism is preferable for cardiac, renal, or vascular disease remains unresolved.
• 03How to dose a short-half-life peptide clinically. PEGylated and acylated analogues show promise in animals, but no stabilized ELABELA has cleared human safety testing.
• 04Whether circulating ELABELA is a useful biomarker independently of known markers in CKD, heart failure, and pulmonary hypertension, or whether it mostly duplicates established risk signals.
• 05The identity of the primary adult tissue sources of circulating ELABELA in humans, given that rodent data (heavy kidney expression) may not directly mirror human biology.
• 06Whether ELABELA and apelin act synergistically, antagonistically, or competitively in adult cardiovascular and renal physiology — evidence suggests all three occur in different contexts (e.g. competitive regulation of coronary angiogenesis).
• 07Long-term safety of APJ activation in reproductive-age patients, given ELABELA's essential role in embryogenesis.

Forms & Administration

ELABELA is not available as an approved therapy. Preclinical work uses synthetic ELABELA-32 or shorter isoforms administered by IV or subcutaneous infusion, with PEGylated and acylated analogues in development to extend the short native half-life. For wellness-audience readers: there is no validated exogenous ELABELA protocol, no approved formulation, and no clinical path currently available outside of research settings.

Common Questions

Safety Profile