Capsids that grip human TfR1

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Qin Huang, Ken Chan, Benjamin Deverman (senior author) and colleagues (24 authors), Broad Institute. Science 384(6701):1220–1227, 2024; funded by the US National Institutes of Health (NINDS and NIMH grants). Apertura Gene Therapy (established in 2021) announced TfR1 capsids, developed in collaboration with Deverman's lab, on 5 January 2024; the paper's competing-interest statement was not read.

What happened

Transferrin receptor 1 (TfR1) is a doorway on brain blood vessels that carries iron into the brain. Because PHP.B relied on a mouse receptor (landmark 254), the team engineered a capsid to bind the human receptor instead.

• BI-hTFR1 binds human TfR1 and is actively carried across human brain endothelial cells in the lab.
• In mice with the human TFRC gene, brain reporter expression was about 40 to 50 times higher than with AAV9. The boost was absent in ordinary mice, so it needs the human receptor. The capsid was also actively carried across human brain endothelial cells in the lab.
• Used to carry GBA1 (the Parkinson's risk gene), it raised brain and spinal-fluid glucocerebrosidase activity above AAV9 (the abstract says "substantially" and gives no multiple).

Why it moved us toward a cure

Gene therapy for Parkinson's, such as GBA1 replacement or switching off SNCA, needs many neurons reached from a vein, not one injection. This design aims the capsid at a human receptor, the route landmark 111 left open.

Outcome

Open. Evidence is in mice and cells only. Apertura's claims of low liver uptake and low-dose effect come from its press release and were not checked; the release makes no primate claim. Apertura now names a second-generation capsid, TfR1 CapX, as its lead (company website, undated); no primate or human data for BI-hTFR1 were found on 20 Oct 2026. Voyager's primate-tested capsid, VCAP-102, uses a different receptor, ALPL (landmark 306).

Sources

• Huang et al., Science 2024, DOI 10.1126/science.adm8386, PMID 38753766 (abstract via Europe PMC; science.org blocked; no correction or retraction listed; preprint bioRxiv 2023, DOI 10.1101/2023.12.20.572615)
• Apertura announcement, 5 Jan 2024 (Pharma Focus Europe)
• Not yet verified: the full Science paper; any primate or human data for BI-hTFR1; the GBA1 fold-change (landmark 111 may quote 30-fold; the abstract gives none); this overlaps the 2024 paragraph of landmark 111.