Treatment With MeCP2 Protein Extends Lifespan in Rett Mice
Treatment with a modified version of the MeCP2 protein, one designed to better get into cells, markedly extended lifespans in a mouse model of Rett syndrome, a study reports.
The MeCP2 protein here was modified by adding a sequence derived from the human immunodeficiency virus (HIV) — a virus known for its attack on the body’s immune system.
Once additional tests are done to ensure its safety and determine the best method of administering it, this approach “has the potential for a rapid transition to human clinical trials” for Rett syndrome, according to researchers.
The study, “TAT-MeCP2 protein variants rescue disease phenotypes in human and mouse models of Rett syndrome,” was published in the International Journal of Biological Macromolecules.
Rett syndrome is chiefly caused by mutations in the MeCP2 gene, which codes for a protein of the same name. There are two variations, or isoforms, of the MeCP2 protein: MeCP2e1 and MeCP2e2. The former is more commonly expressed in the brain.
The protein helps to regulate how DNA is stored within the cell, which affects how various genes are “read.”
Theoretically, restoring levels of MeCP2 protein could help to reverse neurological abnormalities that develop in Rett syndrome. However, the MeCP2 protein needs to get inside of cells in order to function, and cells will not normally take up the protein.
A potential strategy to overcome this problem is the use of protein transduction domains, or PTDs, which are essentially small pieces of protein that act like a sign reading “let me in.” These PTDs prompt cells to take up the protein. To date, one of the best-studied PTDs is derived from an HIV protein called TAT.
Now, an international team of scientists conducted a series of tests to see whether an MeCP2 protein fused to a TAT could be used as a therapy in Rett syndrome.
“The primary aim of this work is to utilize TAT-MeCP2 fusion constructs to assess the functionality and utility of protein replacement therapy for” Rett syndrome, the scientists wrote.
In initial tests, the researchers used TAT-MeCP2e2 to treat fibroblasts (structural cells) derived from a person with Rett syndrome. In these cells, histones — protein structures used to hold DNA in place — had undergone a molecular modification called hyperacetylation, which is characteristic of Rett syndrome. Treatment with TAT-MeCP2e2 reversed this biochemical change.
TAT-MeCP2e1 or TAT-MeCP2e2 then was used — given via injections into the abdomen — to treat mice with Rett-like disease. Results showed that these fusion proteins could effectively get into the mice’s brains. Treatment with TAT-MeCP2e1, but not TAT-MeCP2e2, led to an increase in the size of neurons (nerve cells) in the hippocampus, a region of the brain associated with memory.
“This work clearly demonstrates that TAT-MeCP2 fusion proteins can readily reach brain cell nuclei in amounts that are sufficient to alleviate disease phenotype [observable traits] in a [Rett] mouse model,” the researchers wrote.
“Mice treated with the TAT-MeCP2e1 isoform, but not TAT-MeCP2e2, exhibited normal neuronal [cell body] size in comparison to the untreated group,” they added. “These findings may reflect a specific function for MeCP2e1, at least in hippocampal neurons.”
Untreated Rett mice lived for about 56 days on average. By comparison, mice treated with TAT-MeCP2e1 lived more than 92 days on average, and mice given TAT-MeCP2e2 had an average lifespan of just under 85 days. This translates to a 62.5% increase in lifespan for TAT-MeCP2e1, and a 48.8% longer lifespan for TAT-MeCP2e2.
“While TAT-MeCP2e2 administration does result in a markedly increased mice lifespan, an even longer survival time as well as normal neuronal morphology [structure] is observed in mice injected with TAT-MeCP2e1, suggesting a more vital role for MeCP2e1 in” the disease development of Rett syndrome, the investigators wrote.
Collectively, these results serve as a proof-of-concept for using TAT-fused MeCP2 proteins as a therapy in Rett syndrome. The researchers stressed that more work is needed to evaluate safety and determine the best way to administer these modified proteins as a therapy. However, the team speculated that this approach could be rapidly translated to clinical trials in people with Rett syndrome.