Future treatments of genetic diseases Flashcards
under development “translation research”
pharmacologic chaperones stop codon read-through RNA interference genome editing stem cell therapy gene therapy
chaperones help nascent proteins to
fold properly
pharmacologic charperones are
potent small molecule reversible competitive enzyme inhibitors. At inhibitory concentrations, these active site directed molecules bind to and induce/enhance conformational stability of the mutant enzyme at neutral pH in the endoplasmic reticulum.
function of pharmacologic chaperones
they enable/enhance proper transit from the Er for processing and trafficking to the site of function where the chaperone is displaced by high substrate concentration.
pharmacologic chaperone therapy
increased enzymatic activity predicts clinical benefit
orally administered
biodistribution to sites inaccessible to other therapies.
Kalydeco
a pharmalogic chaperone developed for cystic fibrosis. kalydeco is designed to improve the protein’s function once it has reached the cell surface.
chaperone Vx-809
a pharmacologic chaperone developed for cystic fibrosis. It moves the CF protein with deltaF508 mutation to the cell surface.
most common CF mutation
delta F508. It creates a defective protein that does not move to its proper place at the cell surface.
results from a phase 2 clinical trial of Kalydeco and VX-809 in multiple combinations showed significant improvements in
lung function in people with two copies of the deltaF508 mutation.
chaperone VX is designed to
move the defective delta F508 to the cell surface.
the triple combination of of the corrector VX-440 with tezacaftor (VX-661) and ivacaftor has the potential to
benefit people with CF who are homozygous and heterozygous for the F508 del mutation.
cavosonstat (for CF) works by
inhibiting an enzyme called S-nitrosoglutathione reductase, which is thought to modulate the unstable and defective CFTR protein.
when GSNOR is blocked,
GSNO levels are restored.
This modifies the chaperones, which are responsible for CFTR degradation, and stabilizes the CFTR protein.
In preclinical studies, cavosonstat was shown to
increase and prolong the function of the CFTR protein, leading to an increase in net chloride secretion.
aminoglycoside antibiotics such as gentamicin influence
the fidelity of reading of the stop-codon recognition process and enhance the exent of read-thorugh so that a stop codon could be misread as coding for an amino acid.
eteplirsen
it directs cellular mchinery to skip exon 51.
This allows enough dystrophin production to essentially transform Duchenne muscular dystrophy to Becker, a less severe form of the disease.
long double stranded RNAs can be used to
silence the expression of target genes in a variety of organisms and cell types.
upon introduction the long dsRNAs enter the
RNA interference RNAi pathway.
RNAi pathway
the dsRNAs get processed into 20-25 nt long siRNAs by an RNase III like enzyme called dicers.
The siRNAs assemble into RNA induced silencing complexes. The siRNA strands guide the RISCs to complementary RNA molecules, where they cleave and destroy the RNA.
gene therapy
a technique that uses inserted inserted wild type genes to treat or prevent disease.
gene therapy can involve
replacing a mutated gene that causes disease with a healthy copy of the gene.
inactivating, or “knocking out” a mutated gene that is functioning impropoerly
introducing a new gene into the body to help fight a disease.
ex vivo gene transfer
gene introduced via virus -> transduce in vitro -> return to patient -> explant cells
