Leptomeningeal Disease Secondary to Thr60Ala Transthyretin Amyloidosis: Case Report and Review of the Literature

Carberry, Nathan; Sun, Yu; Fayerman, Raisy; Dugue, Rachelle; Miller, Michael L.; Tanji, Kurenai; Goyal, Tarini; Canoll, Peter; Brannagan, Thomas

doi:10.1177/19418744221127849

Cited by 2 publications

(2 citation statements)

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“…77 CNS deposition following siRNA treatment has also been reported, such as a recently published case of leptomeningeal disease secondary to amyloidosis. 78 Additionally, long-term risk of ocular manifestations has been noted after liver transplantation and ATTR stabilization, due to intraocular production and deposition of mutant TTR in patients with prolonged survival. 76,79 These tissue compartments, however, are protected by the bloodbrain barrier and inaccessible to current RNA silencers and gene editors administered by parenteral routes of delivery.…”

Section: Advantages and Challenges Of Hepatic Targeted Rna Silencers ...mentioning

confidence: 99%

“…CNS complications have been increasingly noted in patients following liver transplantation, suggesting that long‐term survival may lead to amyloid deposits from CNS‐synthesized mutant TTR—a complication not commonly reported in the natural history of the disease 77 . CNS deposition following siRNA treatment has also been reported, such as a recently published case of leptomeningeal disease secondary to amyloidosis 78 . Additionally, long‐term risk of ocular manifestations has been noted after liver transplantation and ATTR stabilization, due to intraocular production and deposition of mutant TTR in patients with prolonged survival 76,79 .…”

Section: Advantages and Challenges Of Hepatic Targeted Rna Silencers ...mentioning

confidence: 99%

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Liver‐directed drugs for transthyretin‐mediated amyloidosis

Brannagan

Berk²,

Gillmore

et al. 2022

J Peripheral Nervous Sys

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Transthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

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