Rare Disease Report

What Hope Exists for Rett Syndrome Patients?

APRIL 02, 2018
Mathew Shanley
While possible therapeutic approaches for Rett syndrome are under development and have the potential to lead to a “cure” for the condition, there are potential obstacles to each being both safe and effective.

An article by Angus John Clarke of the Cardiff University School of Medicine and Ana Paula Abdela Sheikh of the University of Bristol School of Physiology, Pharmacology & Neuroscience, both in the United Kingdom (UK), titled “A perspective on ‘cure’ for Rett syndrome,” concluded that therapies should focus on improving patients’ quality of life (QOL), and expectations for a radical, rational treatment should not be “inflated beyond cautious optimism.”

Results from a study recently published in the Orphanet Journal of Rare Diseases report that behavioral interventions, like environmental enrichment, can reduce the functional deficit experienced by patients with Rett syndrome.

“Toddlers and younger children with Rett have a very good chance of experiencing a major improvement from new types of treatment and even, perhaps, a cure,” the study’s researchers said. “For those further through childhood, the answer may be a middle ground where we hope for the best but prepare for the worst. If there is one lesson that the history of therapeutic discoveries has taught us, it is that throwing money at the problem is no guarantee of the outcome you hoped for. While that shouldn’t stop us from seeking a cure, perhaps we should not give up the search for therapies that bring benefit without necessarily achieving a cure. After all, a child with Rett syndrome now will probably be a young adult by the time “the cure” has first been developed and then made readily available.”

The MEPC2 gene mutation, the underlying cause of Rett syndrome, was only discovered recently, and what has been learned since then has been considered valuable in the development of potential therapies. The mutation has major consequences for motor and cognitive development, and one of the effects of impaired MECP2 function is reduced production of Brain Neurotrophic Factor (BDNF), a protein required for normal neuronal development.

The MEPC2 mutation is not lethal in utero in males, and it is simply more common in females because de novo mutation in the gene happens more commonly in the production of sperm than of eggs, and therefore on the X chromosome passed on from the father. Because the person who carries the mutation is deficient in the MEPC2 protein from the time they begin to grow and develop, it has been said that Rett syndrome appears to be a neurodevelopmental disease because of a “necessary coincidence.”

One of the most widespread challenges to delivering a permanent cure for the condition is that the amount of protein needs to be precise in each brain cell, as too much MECP2 protein can be as detrimental as too little; scientists call this the “Goldilocks principle.” Chances of overcoming the issue are based on inactivation of the X-chromosome, which could potentially resume production of functional MECP2 protein from the intact copy on the other X chromosome. This is an appealing treatment option as cells would utilize their own regulatory functions to generate the correct amount of MECP2 protein.

It is believed that the gene editing technology CRISPR/Cas9 could correct most of the MECP2 mutations that cause Rett syndrome and overcome the “Goldilocks” issue by searching for the specific DNA sequence and removing it. Unlike exon skipping therapy, CRISPR/Cas9 methodology can be more exact in its manipulation of the gene.

Because previous mouse studies have shown that the technology is occasionally not accurate and could cause mutations in unintended sites, however, it’s likely that the technique will not be approved in humans any time soon.

“By now you are probably asking yourself if you should even hope for a cure. We would reply with a very definite, ‘Yes’, but also with some caution,” the authors noted.

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