Here’s an overview of a new potential treatment for transthyretin (ATTR) amyloidosis.
(thread)
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Transthyretin (TTR) is expressed in liver, is secreted into blood, and functions as vitamin/hormone transporter.
ATTR amyloidosis is caused by abnormal aggregates of destabilized TTR monomers (normally forms tetramers)—either mutant or wild-type—damaging nerves and/or heart.
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Patisiran, developed by @Alnylam, is a lipid nanoparticle (LNP)-delivered siRNA that knocks down TTR mRNA in liver.
In clinical trial, 0.3-mg/kg dose IV every 3 weeks = 81% ⬇️ blood TTR, halting neurologic disease progression with ⬆️ quality of life:
In a proof-of-concept study published in 2018, @intelliatweets demonstrated durable editing of TTR in mouse liver using LNP-delivered CRISPR-Cas9, resulting in >97% ⬇️ blood TTR with single 3-mg/kg LNP dose, stable out to 1 year.
In today’s study, LNPs were used to deliver Cas9 mRNA and #CRISPR guide RNA into hepatocytes in vivo to disrupt TTR gene via non-homologous end-joining (NHEJ).
In hepatocytes, Cas9 efficiently edited TTR & induced same 1-bp insertion 99% of the time—very consistent outcome.
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In non-human primates, there was dose-dependent editing of TTR (up to 73% editing with 6-mg/kg LNP dose, consistent with editing of all hepatocytes) and ⬇️ blood TTR (up to >94% reduction) with single LNP doses, stable out to 1 year.
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In 6 patients with ATTR amyloidosis with polyneuropathy—3 receiving 0.1-mg/kg LNP dose, 3 receiving 0.3-mg/kg LNP dose—there was dose-dependent ⬇️ blood TTR at 1 month after treatment.
0.1-mg/kg dose = 52% ⬇️ (range, 47% to 56%)
0.3-mg/kg dose = 87% ⬇️ (range, 80% to 96%)
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One patient had 96% ⬇️ blood TTR—essentially complete elimination! (Of note, 2 additional groups of patients receiving higher LNP doses are planned.)
No patient had serious adverse events or significant LFT elevations, with 1 patient having a mild infusion-related reaction.
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The investigators did note the potential for off-target editing at 7 sites in the human genome—observed in 1º human hepatocytes in vitro only at much higher LNP doses than would ever be used in patients—though all are in noncoding DNA (less likely to affect gene function).
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In sum, this is a remarkable demonstration of efficacy and safety of a totally new therapeutic modality in a first-in-human study.
Many congratulations to the team responsible for this groundbreaking accomplishment!
We asked: are there more PCSK9’s to be discovered?
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We scoured the literature and found that Dr. Gustav Schonfeld @WUSTLendo—an Auschwitz survivor, an immigrant to the US, a foremost expert on lipid metabolism—had identified 4 *healthy* siblings with a “double whammy”:
Lulu and Nana, humanity’s first gene-edited babies, both have some CRISPR edits in the CCR5 gene, as He Jiankui (JK) attempted. His goal was to confer HIV resistance.
Unfortunately, the editing turned out quite badly, as shown by *his own data* in *his own manuscript*. (thread)
This is a Sanger sequencing chromatogram of a PCR amplicon of the CCR5 target site, using DNA from cells extracted from Lulu’s embryo prior to pregnancy.
In the manuscript, JK claims there’s a wild-type allele and a 15bp deletion allele.
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Strangely, in his single public talk about Lulu and Nana in Hong Kong, JK showed the same exact data—but he mislabeled Lulu’s embryo’s edits, mixing them up with Nana’s.
JK’s manuscript (and the chromatograms) makes it clear:
Today is the 1-year anniversary of @antonioregalado breaking the news about Chinese scientist He Jiankui (JK) using gene-edited human embryos to establish pregnancies.