Purified MeCP2: An Alternative Potential Cure For Rett Syndrome.
Recognised strategies to cure Rett Syndrome include gene therapy using adeno-associated virus (AAV) to deliver a functional MeCP2 gene, gene correction by diverse strategies which correct the mutation in the gene and X-chromosome reactivation, possible because cells in females with Rett Syndrome contain a functional copy of the MeCP2 gene in the inactivated X-chromosome.
Purified MeCP2 protein to replace the defective MeCP2.
However, other strategies may be possible, including the delivery of purified, functional MeCP2 protein to cells which contain a defective MeCP2 protein. A recent study, entitled Expression, Purification, Characterization and Cellular Uptake of MeCP2 Variants by Alexander V. Beribisky, Hannes Steinkellner, Sofia Geislberger, Anna Huber, Victoria Sarne, John Christodoulou and Franco Laccone published in The Protein Journal established the basic procedures necessary to establish such a strategy. This study is of particular interest to Australian Rett families as Professor John Christodoulou, one of the authors, is an experienced Rett clinical researcher in the Murdoch Children’s Research Institute, Melbourne.
How does it work?
The investigators expressed and purified different forms of the MeCP2 protein, including the mini-MeCP2 protein, shown previously by Professor Adrian Bird to adequately fulfil the functions of the full-length MeCP2 protein, while other constructs contained a small protein derived from the HIV Tat protein that acts as a carrier to deliver proteins into cells. The study described an effective method to purify the MeCP2 protein and used a number of sophisticated methods to show that the full-length and mini-MeCP2 proteins which were linked to the Tat protein could be relocated into cultured cells, by simply adding the purified protein(s) to the cell culture medium. MeCP2 proteins which were not linked to the Tat protein did not have this ability.
Caveats.
Although the investigators have yet to show that transfer of a functional MeCP2 gene in this manner can correct the deficiencies associated with a mutant MeCP2 protein, we should not lose sight of the fact that any strategy to deliver a functional MeCP2 protein has the potential to cure or alleviate many of the clinical characteristics associated with Rett Syndrome. This is the first step in the process, and as previous investigators have shown that Tat-linked proteins can gain access to the brain by crossing the blood-brain barrier, this has the potential to lead to a simple injection of the MeCP2 protein that will migrate to the brain where the Tat-linked MeCP2 protein will be taken up by neurons.
There are of course many obstacles to overcome but the strategy has several advantages, including simplicity and the fact that multiple doses can readily be delivered depending on the clinical response. We will look forward to hearing of the next stage in the overall research plan.
Eric Gowans, Adelaide
