Gene Therapy Strategies: Gene Augmentation

Ataluren—Promising Therapeutic Premature Termination Codon Readthrough Frontrunner

“…A nucleic acid-based technology characterized by a simple design that could also be used to correct nonsense mutations is a groundbreaking Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing. It is based on sequence-specific endonucleases cutting both strands of a DNA duplex in the vicinity of the site to be edited, which is followed by the endogenous DNA repair mechanism introducing changes in the nucleotide sequence [ 13 ]. Alternatively, deactivated versions of the nuclease conjugated with an adenosine deaminase can be used.…”

“…CRISPR gene editing has drawbacks, too. It is prone to off-target effects since mismatches in the complementary nucleotide sequence can be tolerated [ 13 ]. Despite their limitations, the three above-mentioned approaches are invaluable, since they target the underlying cause of the disease, not just its symptoms, and hopefully more and more safe and effective therapeutics able to suppress disease-causing PCTs will be approved for the treatment saving precious lives.…”

“…The readthrough therapy has many advantages comparing to alternative approaches such as gene augmentation, which enables the introduction of an additional functional wild-type gene using a vector [ 13 ]. Namely, no random integration of DNA or alternative splicing is possible.…”

Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias

“…The gene therapy augmentation strategy is a simple and straightforward method where a new protein-coding gene is added to a target cell or organ [ 34 ]. This method is particularly suitable for monogenic recessive diseases, where only adding one copy of the normal allele is enough for phenotype reversion, and ultimately cure the disease.…”

“…This specific strategy can also be named as gene replacement therapy, in the context where the dysfunctional or the lack of a protein is overcomed by adding the correct version of the coding gene. However, for monogenic dominant or complex diseases, as in case of PolyQ SCAs, this approach is not sufficient, and therefore other strategies, such as, gene silencing or gene editing would have a better outcome in reverting the disease phenotype [ 34 ]. While this is true, several studies have shown that gene addition therapy could be useful in the context of PolyQ SCAs.…”