David Lieberman, MD, PhD: The role of gene therapy in Rett syndrome is a tricky one. What’s interesting about the MECP2 gene is that if there’s a mutation and the function of the gene is impaired, you have less MECP2 gene, you have Rett syndrome, [and you] have a few symptoms.

If you overexpress MECP2, you can get what’s called the MECP2 duplication syndrome, where those individuals also have a number of neurologic problems. They have communication deficits, they have hand function deficits, and they have seizures. The expression of MECP2 has to be tightly regulated. There’s not too much gene expressed because of the gene therapy. There are companies that are developing some regulatory elements…that will permit the gene to be expressed in much lower amounts in cells that already have normal MECP2 levels. In those cells, where there’s lower MECP2 levels, the gene therapy would boost the MECP2 content in that cell. There is already 1 company, Taysha Gene Therapy, that launched a trial in women [aged 18 and older] with Rett syndrome in Canada. I don’t know if anyone’s been dosed yet, but at least that is an imminent trial. I think that trial may also come to the United States. There’s another company, Neurogene, that’s also working on a similar project. What’s interesting about both gene therapies is we know that MECP2 has downstream effects on several genes. It’s a regulator of transcription as both a transcription activator and a transcription repressor. Although the number of downstream targets is very large, the actual impact of that regulation is small. It’s really the impact of lots of small changes on a lot of genes that that produce Rett syndrome. I don’t think that the drugs that we would use can mimic the same type of pharmacology or actions on several different cellular processes; it just it’s too vast, too wide. They don’t all coalesce into a particular metabolic pathway. I think that gene therapy has the promise of improving the lives of our patients with Rett syndrome in ways that traditional pharmaceuticals wouldn’t be able to do.

The goals of therapy, as I see it for Rett syndrome, should be treating the symptoms that are kind of comorbid with Rett syndrome, as well as trying to treat, as best we can, some of the core features, including the hand function, communication, repetitive hand stereotypies, and ambulation. We also have to do it in such a way that it’s not too burdensome to the patient or to the family. We try to avoid medications that are too sedating for patients, which could reduce their quality of life. We have to balance medications and other [adverse] effects so that there aren’t interactions between some of the drugs, since there are a lot of medications that we’re using.

Transcript edited for clarity.