Rett syndrome is a genetic neurodevelopmental disease caused by mutations in the MECP2 gene.

Currently, there is no cure for Rett syndrome, but scientists are working to find a treatment that can change the course of the disease. RNA repair is one of several approaches, but it is still in the early stages of development.

How MECP2 RNA repair works

DNA contains the genetic information and is stored in the cell nucleus. Genes within the DNA provide information on how to build a specific protein, such as MeCP2. RNA serves as an intermediary that carries this information outside the nucleus to the cytoplasm, where proteins are made using the RNA as a template. Because MeCP2 is a transcription factor, or a protein that controls the activity of other genes, it is then transported back into the nucleus.

In Rett syndrome, the MECP2 gene still produces MECP2 RNA, which serves as a template to build MeCP2 protein, but because of errors in the genetic code, the protein product is not functional.

Researchers think that by repairing MECP2 RNA, the cell can be made to produce functional MeCP2 protein. With this approach, the amount of protein produced would not be altered, which is critical because too much MeCP2 protein can be harmful. Being able to keep the protein level in a healthy range is an advantage of this approach over gene therapy, where healthy MECP2 gene copies are delivered to the cell. But it is difficult to accurately dose the number of delivered copies, easily providing too many.

Spliceosome-mediated RNA trans-splicing therapy

The RNA transported into the cytoplasm is not the final blueprint for making the protein. It contains some regions, called introns, that are cut or spliced out before the protein is made. The RNA parts that serve as a template for the protein are called exons.

Spliceosome-mediated RNA trans-splicing therapy (SMaRT) delivers engineered RNA molecules that still contain one of these introns, intron number 2. Most mutations causing Rett syndrome lie within exon 3 and 4, which are situated just after intron 2. Intron 2 from the engineered RNA molecule can bind to intron 2 within the mutated MECP2 RNA. During the splicing process, the correct exon 3 and 4 from the engineered RNA help to produce intact MECP2 RNA.

Repair of G > A point mutations

RNA consists of four different building blocks, so-called bases, which are represented by the letters A, C, G, and U. One type of mutation that can occur within the MECP2 gene is a point mutation. In a point mutation, one of these bases is replaced by another base. One mutation that can occur is a G > A transition, where the original G base has been replaced by an A base.

There is a known enzyme that can restore the A base into a G base. Researchers try to use this enzyme to correct G > A mutations within the MECP2 gene. However, the G > A mutation is not very common, so this approach would only be beneficial to a small group of patients even if clinically developed.

New RNA editing enzymes

ADAR enzymes can also correct point mutations, and they work by a different mechanism than the enzymes that fix G > A mutations. One team of researchers developed efficient versions of these enzymes. The goal is to develop a therapy that would be administered as a one-time treatment.

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