Reversing three genetic diseases in the animal model without even changing a single DNA letter. A Salk Institute team did it by bringing together two of biomedicine’s hottest trends. One is the CRISPR technique, which edits target genes through a programmable molecular machine named Cas9. The other is epigenetics, i.e., the study of chemical modifications that switch genes on and off without altering their sequence. It’s called epigenetic editing, because corrections are precise as in manuscript revision and occur at a level that is over (epi- in Greek) genetics.
The first-ever demonstration that scientists can epi-genetically edit the phenotype of mice preserving DNA integrity was published in Cell last week. The recipe developed by Juan Carlos Izpisua Belmonte and colleagues employs adeno-associated viruses as carriers, and the ingredients are separately delivered because, if taken together, its load would be too heavy. Therefore instructions coding for Cas9 are packaged into a virus, while its RNA guide and the transcriptional activator for the epigenetic task are inserted into another virus. What you get is a CRISPR variant accessorized to promote gene transcription. Faulty genes responsible for the pathologies of interest, in short, can be left as they are, because genetic defects can be compensated by increasing the expression of other well-functioning genes in the same pathways as the damaged genes. In this way, the hurdle is overcome rather than being removed.
The Salk Institute researchers first showed that a normal kidney function could be restored in a mouse model with acute kidney disease by over-expressing a gene which protects against renal damage (klotho) and another gene with anti-inflammatory function (interleukin 10). Then they succeeded in controlling hyperglycemia in a mouse model of type I diabetes, by over-expressing the Pdx1 gene in liver cells and transdifferentiating hepatocytes into pancreatic insulin-producing cells. Finally, they targeted Duchenne dystrophy by restoring klotho expression or by upregulating a gene coding for a protein very similar to dystrophin (utrophin). Belmonte hopes that the same approach will work for neurological disorders as Alzheimer and Parkinson, but further studies are required to ensure safety and efficiency before the technique can be considered for human trials.