Precision Medicine: the Present and Future of the Treatment of Mendelian Disease

The treatment of single-gene diseases embodies the concept of precision medicine tailored to the individual patient as deeply as any other area of medical treatment. Knowledge of the specific mutant sequence in an individual is central to many of the targeted therapies described in this chapter. The promise of gene therapy for an individual with a mendelian disorder must be based on the identification of the mutant gene in each affected individual and on the design of a vector that will deliver the therapeutic gene to the targeted tissue. Similarly, approaches based on gene editing require knowledge of the specific mutation to be corrected.

Beyond this, however, precision medicine will frequently require knowledge of the precise mutant allele and of its specific effect on the mRNA and protein. In many cases, the exact nature of the mutation will define the drug that will bind to a specific regulatory sequence to enhance or reduce the expression of a gene. In other cases, the mutation will dictate the sequence of an allele-specific oligonucleotide to mediate the skipping of an exon with a premature termination codon, or of an siRNA to suppress a dominant negative allele. A compendium of small molecules will gradually become available to suppress particular stop codons, to act as chaperones that will rescue mutant proteins from misfolding and proteosomal degradation, or to potentiate the activity of mutant proteins.

Genetic treatment is not only becoming more and more creative, it is becoming more and more precise. The future promises not only a longer life for many patients, but a life of vastly better quality.