Mutation-driven disease mechanisms and implications for gene therapy (IMAGE)
Caption
(Top) Point mutations (red star) in the DNA give rise to mutant mRNA and polypeptides that either misfold and are degraded—resulting in loss‐of‐function—or evade quality control to form toxic assemblies that interfere with normal cellular processes (dominant disease).
(Bottom left) In loss‐of‐function disorders, viral‐vector-mediated gene augmentation can supply a functional copy of the gene to restore wild-type protein expression. However, overexpression, as exemplified by Friedreich’s ataxia, can itself be toxic, highlighting the need for precise control of transgene dosage.
(Bottom right) In dominant or toxic‐gain‐of‐function diseases, simple gene addition is insufficient: effective therapy requires selective silencing or clearance of the mutant allele (and its toxic protein) before a healthy copy can be introduced to reestablish normal cellular function.
Credit
Diego di Bernardo
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