Original title: Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis
Daniela Ricci, Chloé Veront, Irene Valcozzena, Merlin Després +11 · September 2026
In AL amyloidosis, abnormal immune cells called plasma cells make unstable proteins called light chains. These proteins leave the cell and cause harmful organ damage, but no current treatment directly stops cells from building them. Researchers tested a way to shut down light-chain production by blocking Sec61, a protein channel that cells use to import newly made proteins. When researchers blocked Sec61 with a compound called mycolactone, cells degraded the light chains instead, which triggered stress and boosted the effect of the cancer drug bortezomib. While this drug pair caused toxic side effects in living models, synthetic blockers called A317 and A347 showed more selective targeting. A317 blocked many diverse light chains, lowered pathogenic light-chain output in primary patient cells, and spared non-cancerous bone marrow cells.
Imagine you run a small bakery and every morning you bake a special cake to ship to customers. Normally, you slide the cake down a chute into the delivery van. Now suppose someone installs a grate over the chute, so the cake falls into a grinder instead. In this paper, the chute is a protein channel inside the cell, the cake is a toxic protein, and the grate is the drug. Blocking the channel makes the cell destroy the protein instead of secreting it, so it never gets a chance to clump and damage organs.
AL amyloidosis is a rare blood disease where rogue plasma cells secrete misfolded antibody fragments that build up in organs and cause damage. Current treatments don't directly stop the production of these toxic proteins. This research shows that blocking a specific cellular channel can reduce their production while sparing healthy bone-marrow cells, pointing toward a more targeted therapy.
The in vivo combination caused systemic toxicity, so the approach is not yet safe. The more selective inhibitor A347 failed to block diverse amyloidogenic light chains, showing a trade-off between selectivity and coverage. The findings are based on cell lines and primary patient cells, not clinical trials, and the abstract does not specify the animal model or the nature of the toxicity.
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Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis — Daniela Ricci, Chloé Veront, Irene Valcozzena et al. — bioRxiv — doi:10.64898/2026.09.10.750585
Abstract licence: CC BY
Explanation generated by Synthesis from the abstract — it is not the original paper. This is a preprint, so it hasn't necessarily been peer reviewed.