New Therapeutics, Gene Therapies Show Promise in Rett Syndrome


Session at the 2023 Asembia Summit notes that pharmacists play a particularly important role in the large multidisciplinary care team needed for Rett syndrome management.

With the recent FDA approval of trofinetide (Daybue, Acadia) and other pharmaceuticals and gene therapies in the pipeline, pharmacists can play a crucial role on the care team for patients with Rett syndrome (RTT) and their families, according to a presentation at the 2023 Asembia Summit.

Credit: Vitalii Vodolazskyi -

Credit: Vitalii Vodolazskyi -

RTT is a rare, severe, neurodevelopmental disorder affecting 1 in 10,000 to 15,000 live female births, according to presenter Abigail Jastrab, PharmD, BCPS. Although it is a rare disease, RTT is the second leading cause of intellectual disability in girls. Although it can occur in boys, RTT almost entirely occurs in girls.

The unique disorder is characterized by normal development in the first 6 to 18 months of life, followed by the loss of development and other characteristics such as apraxia, repetitive hand movements, gait abnormalities, and cognitive impairment. It is associated with a mutation in the MECP2 gene on the X chromosome, which is a critical reader of DNA methylation and regulating gene expression.

“This mutation is almost always spontaneous and not expected to recur within families,” Jastrab explained.

RTT is diagnosed as either typical or atypical. In typical RTT, approximately 92% of patients have MECP2 mutations, whereas between 50% and 75% have these mutations in atypical RTT. For both types, however, the key point is that the patient has periods of regression followed by recovery or stabilization.

For instance, the first symptoms can begin around 6 months and include issues with sitting, crawling, or walking; lack of interest in toys; abnormal hand movements; and problems with speech development. After this, however, patients may recover or stabilize.

Stage 2 is characterized by the loss of previously acquired motor, communication, and social skills, as well as the loss of ability to use hands purposefully. This stage begins around age 1.

Stage 3 begins around 2 years of age and is a plateau stage during which caregivers may even see slight improvements. However, it can also be accompanied by seizures, worsening breathing problems, cardiac arrhythmias, and difficulty gaining or maintaining weight.

“We also see improved eye contact [in this stage], which becomes a very important way to communicate with these girls,” Jastrab said.

Finally, stage 4 is characterized by reduced mobility, muscle weakness, joint stiffness, scoliosis, and the loss of walking ability. This stage can begin around 10 years of age.

Importantly, the life expectancy for patients with RTT has improved considerably since the disorder was first identified. More than 75% of patients now live to 50 years of age, explained presenter Alan Percy, MD.

“This is not a short-term disorder,” Percy said. “The original group seen by [researcher] Andy Rett in the 1950s and 60s had a survival that didn’t really reach 25 years. In the US, we’ve [now] had several studies that show survival is beyond 50 years in individuals with this disorder.”

Growing understanding of the disorder and treatment options are certainly to thank for this longer life expectancy. Treatment of RTT is multifactorial, based primarily on symptom management to promote optimal health, as well as specific therapeutic strategies based on new clinical trial results and additional trials.

Approved on March 11, 2023, trofinetide is a novel synthetic analog of glycine-proline glutamate, a protein that is found in the brain to partially reverse Rett syndrome-like symptoms in the MECP2 gene. It was originally found to be efficacious in mice studies, and although an initial human trial found no efficacy, a modified product was found to be safe, well-tolerated, and efficacious.

The phase 3 LAVENDER study was a double-blind, placebo-controlled trial with 93 participants in the treatment arm and 94 in the placebo arm. The primary endpoints were caregiver-reported change in Rett Syndrome Behavioral Questionnaire (RSBQ) and the Clinical Global Impression–Improvement Scale (CGI-I).

“Communication in this [trial] was significantly improved. After 12 weeks, both the CGI-I and the RSBQ showed significant improvements,” Percy said, emphasizing that communication is by far the most significant concern for caregivers.

The RSBQ score was reduced by 5.1 from baseline in the treatment arm at week 12, compared with a 1.7-point reduction in the placebo arm. Adverse effects included diarrhea and vomiting in approximately 80% and 27% of participants, respectively.

The LILAC study, the 40-week open-label extension of the LAVENDER trial, showed a similar change. By 52 weeks, at the conclusion of both studies, the results were even better than after 12 weeks in the treatment group, Percy said.

Blarcamesine is an investigational sigma-1 receptor agonist and muscarinic receptor modulator. Data suggest that the activation of sigma-1 receptors results in the restoration of homeostatic function in the body, which could be pivotal to restoring neural cell balance.

The AVATAR trial was a placebo-controlled phase 3 study in adults with RTT. At 7 weeks, treatment with blarcamesine produced a statistically significant improvement in RSBQ under the curve in 72.2% of patients in the treatment arm, versus 38.5% in the placebo arm. It also demonstrated a statistically significant reduction in emotional behavioral symptoms.

Finally, Percy said gene replacement trials are particularly exciting for patients, caregivers, and clinicians treating RTT. In 2007, a critical study indicated the reversal of neurological deficits in a mouse model of RTT after replacing the gene, and phenotypic improvements were impressive in both young and mature mice.

Two companies either have or are expected to receive approval for clinical trials investigating this approach. Taysha Gene Therapies is testing the approach in adults with the first patient expected to be treated at the end of May, and Neurogene is launching a trial expected to begin in fall 2023.

With all of these developments, Jastrab said pharmacists play a particularly important role in the large multidisciplinary care team needed for RTT management. In addition to guiding treatment selection, pharmacists often have a vital high-level overview of all of the medications coming from various prescribers, who may not otherwise be communicating.

“Pharmacists are important educators and support for those with Rett syndrome,” Jastrab said. “They provide support to both the patient, the caregiver, and the provider.”

As the most accessible providers, pharmacists also interact with patients much more often than other clinicians, offering much-needed opportunities to counsel and hear about adverse effects or other issues.

“Pharmacists are in a unique position with their unique access and frequent touchpoints with these patients and caregivers,” Jastrab concluded.


Jastrab A, Percy A. Evolving Treatment Landscape of Rett Syndrome: Emerging Therapies to Address Critical Clinical Gaps. Presented at: Asembia Summit 2023. May 1, 2023. Accessed May 1, 2023.

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