1-28 Novel therapies for genetic disorders Flashcards
gene product replacement
supplement with native protein: usually parenteral, stable in blood and intracellularly, targeted to correct cell type/organelle
often need to modify proteins to achieve this: modify glycosylation pattern, fusion proteins
ex: Gaucher disease: modify the exposed glycosylation side chain of the glucocerebrosidase to target to macrophages for uptake (prefers mannose, so exposed), enzyme replacement therapy
ex: Achondroplasia: FGFR3, landing site for fibroblast growth factor (FGF), is mutated and inhibits proper growth, CNP binds NPR-B and inhibits the mutant FGFR3 signaling that could promote growth! unfortunately CNP has short half life, so we modified it to increase half life and so far growth rate has increased in folks treated with this peptide!
Fusion proteins in treating genetic disorders
stabilize necessary proteins for replacement, ex bind protein of interest to immunoglobulin
Pharmacological chaperones
chemicals which bind to the active site of the enzyme, may help the enzyme fold normally even if it is an abnormal enzyme, now correctly fold enzyme will be transported to the lysosome, in the lysosome the chaperone is released, and the enzyme may act on its natural substrate
for lysosomal diseases this is great!
can be a competitive inhibitor
none currently licensed in USA but in Europe testing
Enzyme inhibition for genetic therapy
ex. statins inhibit HMG coA reductase so reduces cholesterol synthesis which increases LDL receptor synthesis
“Read-through”
certain chemicals are able to prevent termination of translation when a stop codon in encountered
permits translation of genes with stop codons in exons (ie premature termination codons)
may preserve substantial protein function
Ataluren: for CF and Duchenne muscular dystrophy, used to treat kids with these conditions based on having a stop codon in an exon
Alternative splicing editing for genetic therapy
drugs to help change splice sites to modify gene expression, ASOs can bind splice sites and mask them
exon skipping
to exclude inappropriate exons/exons with premature stop codon in it (Duchenne’s muscular dystrophy!)
inhibitory RNAs for genetic therapy
in dominant disorders resulting form gain of function effect ex: huntington disease, caused by expansion of a trinuc repeat, if expression could be suppressed then the healthy allele would be expressed and good!
not yet used in therapy
Blood brain barrier in gene therapy
need to utilize receptor mediated transport from blood to brain because tight junctions of cells do not allow toxins through
LRP1 receptor is one receptor we could use/target drugs to to get into brain
