Biopharm: Oligonucleotides (Foosh)

What are oligonucleotides?

short chains of single stranded or double stranded ribo- or deoxyribonucleotides

What do oligonucleotides bind to?

chromosomal DNA, mRNA, or non-coding RNA (ncRNA)

What do oligonucleotides modulate, and via what process?

gene expression through Watson-Crick base pairing w/ targeted nucleic acids

What micro/macromolecules are included under the umbrella term, oligonucleotides?

antisense oligonucleotides (ASOs), small interfering RNA (siRNAs), microRNA (miRNAs), aptamers, and DNAzymes

Oligonucleotides are very ____ molecules

potent

How are oligonucleotides excreted?

rapidly by the kidneys

idk, know this image

MOA of oligonucleotides

direct binding to non-nucleic acids and interfere with gene expression

Aptamers/riboswitches bind _____ to non-nucleic acids

directly

T/F - aptamers occur naturally, riboswitches are isolated artifically?

F - aptamers are isolated artificially, riboswitches occur naturally

Aptamers/riboswitches __ their target molecule by ____________

bind via complementary shape interactions

What is the target of Pegaptanib (Macugen)?

VEGF

What is Pegaptanib (Macugen) indicated for?

age related macular degeneration

(MACUgen = MACUlar)

In terms of unmethylated cytosine-phosphate-guanine (CpG) motifs dinucleotide sequences, what is the difference between prokaryotic DNA and mammalian DNA?

prokaryotic DNA contain many CpG motifs, mammalian DNA doesn’t

What is the benefit of synthetic oligonucleotides containing CpG motifs?

they can mimic prokaryotic DNA and induce immune responses

CpG 1018 in Heplisav mimics what?

hepatitic B antigen for Hep B vaccine

What are the translation inhibiting oligonucleotides?

antisense oligonucleotides, ribozyme DNAzyme, small interfering RNA

What is the MOA of antisense oligonucleotides?

binds to mRNA, blocking it from ribosomal RNA for translation

What is the MOA of ribozyme/DNAzyme?

bind to mRNA and break it down

What is the MOA of small interfering RNA?

bind to mRNA and RISC protein recognizes the mRNA outside of the nucleus and breaks it down

What is the BBW with mipomersen (Kynamro)?

risk of hepatotoxicity (for a pt to get it, they need to go through strict program called Kynamro REMS)

How is mipomersen (Kynamro) administered? stored?

SUBQ, refrigerated

What is the indication of nusinersen (Spinraza)?

treatment of spinal muscular atrophy (SMA)

(SPINraza = SPINal)

What are concerning adverse effects with nusinersen (Spinraza)?

Hematologic effects (coagulation abnormalities and thrombocytopenia) and renal toxicity (potentially fatal glomerulonephritis)

Which biologics are antisense?

mipomersen (Kynamro), nusinersen (Spinraza), and inotersen (Tegsedi)

MOA and route of admin of inotersen (Tegsedi)

degradation of mutant and wild type TTR mRNA, SUBQ

What are ribozymes and DNAzymes made of?

made of DNA (DNAzymes are artificial and are easier to synthesize)

What are triple helix-forming oligonucleotides?

prevent transcription by binding to DNA helix

Which biologics are transcription factor decoys?

upadacitinib and AMG0103

What is upadacitinib?

NFKB-decoys for atopic dermatitis

What is AMG0103 used for?

chronic discogenic lumbar back pain

What is CRISPR/Cas9 made up of?

TWO key molecules: Cas9 enzyme, piece of RNA called guide RNA (gRNA)

What is CTX001?

investigational ex vivo CRISPR gene-edited therapy for sickled cell anemia and transfusion-dep B-thalassemia

What is the Epson Skipping Approach?

U7 (an oligonucleotide) binds to the mutant exon that we don’t want transcribed, masking the exon and having skipped by RNA polymerase

Which biologics are the Antisense-Mediated Epson Skipping Oligonucleotides?

Casimersen (Amondys 45), eteplirsen (Exondys 51), Golodirsen (Vyondys 53), and vitolarsen (Viltepso)

What are the antisense-mediated epson skipping oligonucleotides indicated for?

Duchenne muscular dystrophy

What are the specific concerns with casimersen (Amondys 45)?

renal clearance is reduced in non-Duchenne muscular dystrophy (DMD) pts w/ renal impairment

What are the specific concerns with eteplirsen (Exondys 51)?

hypersensitivity reactions

What are the specific concerns with Golodirsen (Vyondys 53)?

hypersensitivity reactions, kidney toxicity, including potentially fatal glomerulonephritis

What is the difference between bioavailability after intradermal and subq injections vs oral?

higher bioavailability after intradermal and subq injections, oral is generally very low