Hereditary angioedema (HAE)

What changes during this transition

HAE is one of the clearest examples in this library of a disease where peptide therapeutics have no role and the targeted standard-of-care is the only honest answer. Diagnosis requires C1q + C4 + C1-INH antigenic + C1-INH functional testing, with genetic testing for HAE-nC1INH variants when C1-INH is normal but the clinical phenotype fits. The HAE-nC1INH variant heterogeneity (factor XII, plasminogen, kininogen, ANGPT1, myoferlin, heparan sulfate) means underdiagnosis is real in patients with normal C1-INH but real attack phenotypes. On-demand attack treatment runs through icatibant (Firazyr, B2 receptor antagonist), ecallantide (Kalbitor, kallikrein inhibitor), plasma-derived C1-INH (Berinert IV, Cinryze IV), and recombinant C1-INH (Ruconest). Long-term prophylaxis has been transformed in the last decade: lanadelumab (Takhzyro, FDA 2018) is a subcutaneous kallikrein monoclonal antibody dosed every 2-4 weeks; berotralstat (Orladeyo, FDA 2020) is an oral kallikrein inhibitor; donidalorsen (Wainzua, FDA 2024) is a prekallikrein antisense oligonucleotide from the Phase 3 OASIS-HAE program; subcutaneous C1-INH (Haegarda) provides prophylactic concentrate; attenuated androgens (danazol) persist but are in decline. The paradigm shift now in clinical reach is NTLA-2002 (Intellia), a single-dose CRISPR/Cas9 KLKB1 knockout with Phase 2 data showing >90% attack reduction from one infusion. This is editorially load-bearing because it changes the answer to 'why not just add a peptide on top of standard care': the standard care itself is in the middle of becoming functionally curative for many patients, which raises the opportunity cost of any unproven adjunct. ACE inhibitors are an absolute contraindication in HAE because they block kininase II, the remaining bradykinin clearance pathway; estrogen-containing products are an attack trigger; tissue trauma (including dental work and surgery) is a known precipitant warranting pre-procedural prophylaxis under HAE specialist guidance. Where Juno's library fits — narrowly and with deliberate non-elevation. No peptide in the library has a discovery-card-defensible HAE case. The five drafted substrate entries (BPC-157, TB-500, Thymosin alpha-1, Selank, KPV) exist for honest /ask answers when users probe specific compounds, not for browse elevation. BPC-157's wound-healing framing doesn't engage bradykinin biology and the SC injection itself is a tissue-trauma precipitant. TB-500's 'vascular peptide' framing operates on a different layer of vascular biology than bradykinin-driven endothelial gap formation. Thymosin alpha-1 is Rule 6 non-propagation territory — the hepatitis B registered indication does NOT propagate to HAE because the underlying biology (adaptive immunity vs contact system) is unrelated. Selank addresses the real anxiety overlay but using it for HAE-related anxiety while attacks remain inadequately controlled treats the downstream symptom rather than the upstream disease. KPV's NF-κB-attenuation framing applies inflammatory-edema logic to bradykinin-driven swelling, which is the same category error that emergency departments unfamiliar with the disease sometimes make. The honest editorial frame: immunology / HAE specialist coordination, WAO/EAACI 2021 guidance, the on-demand armamentarium, the prophylactic armamentarium, NTLA-2002 trial enrollment candidacy assessment for severe disease, AE-QoL and AECT tracking, ACE inhibitor and estrogen audit, and HAEA medical advisory board recommendations drive outcomes.