AMB 14- RNA Therapeutics

Comprehensive vocabulary flashcards detailing concepts, molecular mechanisms, formulations, and regulatory advances in RNA therapeutics and vaccines.

Lipid nanoparticles (LNPs)

Spherical delivery vehicles with a diameter of approximately $50\,\text{nm}$ composed of ionizable lipids, phospholipids, cholesterol, and PEGylated lipids, engineered to protect nucleic acids from RNase degradation and enable intracellular delivery.

Pseudouridine ($\Psi$)

A modified nucleoside isomer of uridine synthesized via pseudouridine synthase that suppresses Toll-like receptor recognition and diminishes PKR activation, thereby improving mRNA stability and translational output.

1-methylpseudouridine ($\text{m1}\Psi$)

A chemically modified nucleoside used as a $100\%$ replacement for uridine in the BNT162b2 and mRNA-1273 COVID-19 vaccines to decrease immunogenicity and enhance translation even more effectively than pseudouridine.

Protein Kinase R (PKR)

An intracellular sensor kinase that dimerizes and autophosphorylates upon detecting unmodified foreign RNA, subsequently phosphorylating eIF2$\alpha$ to inhibit protein translation as part of the integrated stress response.

eIF2$\alpha$

A eukaryotic translation initiation factor whose phosphorylation by activated PKR arrests protein translation during the cellular antiviral defense response.

ALC-0315

The synthetic ionizable lipid constituent of the lipid nanoparticle delivery system utilized in the BioNTech/Pfizer BNT162b2 mRNA vaccine.

SM-102

The proprietary ionizable lipid constituent employed in the lipid nanoparticle formulation of the Moderna mRNA-1273 vaccine.

ALC-0159

The PEGylated stealth lipid component incorporated in the BioNTech/Pfizer BNT162b2 lipid nanoparticle to provide immune cloaking and maintain nanoparticle stability.

PEG2000-DMG

The PEGylated stealth lipid used in the Moderna mRNA-1273 lipid nanoparticle formulation to enhance in vivo half-life and colloidal stability.

Distearoylphosphatidylcholine (DSPC)

A structural helper phospholipid included alongside cholesterol in lipid nanoparticles to form and stabilize the lipid bilayer shell.

K986P and V987P substitutions

Two stabilizing proline substitutions introduced into the SARS-CoV-2 full-length Spike glycoprotein encoded in both the BNT162b2 and mRNA-1273 vaccines to maintain the prefusion conformation.

Endosomal escape

The process by which internalized lipid nanoparticle-encapsulated mRNA escapes endosomal acidification and disruption into the host cytoplasm to be translated.

Self-amplifying RNA (saRNA)

An engineered RNA construct containing alphavirus nonstructural genes ($\text{nsP1-4}$) encoding an RNA-dependent RNA polymerase (RdRP) complex that directs intracellular replication of the vaccine immunogen.

Circular RNA (circRNA)

A closed, covalently linked single-stranded RNA loop lacking free $5^\prime$ and $3^\prime$ ends, providing exonuclease resistance, functioning as a sponge for miRNAs or RNA-binding proteins, and translating via cap-independent initiation.

Back-splicing

A non-canonical splicing process in which a downstream $5^\prime$ splice donor site joins to an upstream $3^\prime$ splice acceptor site to generate circular RNA containing a back-splice junction (BSJ).

Internal Ribosome Entry Site (IRES)

A specialized RNA structure that recruits the 40S ribosomal subunit to facilitate cap-independent initiation of translation in circular RNAs or viral transcripts.

Poly(A) tail mimetics

Synthetic oligonucleotide therapeutics consisting of an antisense guide linked to a poly(A) tail mimetic, designed to bind an mRNA $3^\prime$ UTR and prevent deadenylation in haploinsufficiency disorders.

Onpattro (patisiran)

The first FDA-approved RNAi (siRNA) lipid nanoparticle formulation, approved for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis in adults.

Duxil

The first lipid nanoparticle-encapsulated pharmaceutical formulation approved by the FDA in 1995.

KC2 and MC3

Ionizable cationic lipids discovered in 2010 and 2012, respectively, that advanced the efficacy and safety profile of lipid nanoparticles for nucleic acid delivery.

Katalin Karikó

Biochemist whose seminal work revealed that incorporating modified nucleosides into synthetic mRNA suppresses Toll-like receptor recognition and avoids PKR-mediated translational inhibition.

Kizzmekia S. Corbett

Viral immunologist whose structural design of coronavirus Spike protein immunogens and prototype pathogen research enabled the rapid generation of COVID-19 mRNA vaccines.

AMT-130

A clinical gene therapy developed by uniQure that delivers microRNA designed to silence the expression of the mutated gene that drives Huntington's disease.

Cap 1 structure

A mature eukaryotic $5^\prime$ mRNA cap feature that prevents innate immune detection; incorporated into BNT162b2 via a co-transcriptional Cap 1 analogue or generated enzymatically in mRNA-1273.

Stealth lipids

PEGylated lipids situated on the outer surface of lipid nanoparticles that provide immune evasion, prevent premature clearance, and prolong circulation half-life in vivo.