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First-Ever US FDA Approved Treatment for Rett Syndrome

An Interview with Jennifer Martelle Tu, MD, PhD

Director of Katie’s Clinic for Rett Syndrome at UCSF Benioff Children’s Hospital


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Jennifer Martelle Tu, MD, PhD

The US FDA recently approved the first-ever treatment for Rett syndrome, a rare and debilitating neurological disorder diagnosed almost exclusively in girls. We spoke with UCSF’s Director of Katie’s Clinic for Rett Syndrome, pediatric neurologist Dr. Tu, to learn more about the new drug and what it means for the Rett community.

What is Rett syndrome?

Rett Syndrome is a neurodevelopmental disorder that is caused by a genetic mutation on the X chromosome on the MECP2 gene. While it affects protein expression throughout the body, it’s most notable in the brain because at certain times of development, the lack of gene expression leads to poor neurodevelopmental outcomes.

This condition primarily affects girls and typically becomes evident within the first two years of life. Initially, their development follows a normal trajectory, but around 12 to 18 months, they reach a plateau followed by regression, where they experience a loss of manual dexterity and language abilities.

It is important to note that Rett syndrome does not progress as a disorder. Once these girls surpass the regression phase, they can acquire new skills.

How is Rett syndrome diagnosed?

It starts with clinical suspicion where there are concerns about the child’s development when it plateaus, or they start to lose skills. Several hallmark features help identify this condition, such as hand stereotypies, which manifest as repetitive actions like wringing, clapping, or tapping of the hands. Once a clinical diagnosis is made, a genetic test is conducted to detect the presence of the MECP2 gene mutation.

What are the current treatment options?

The current approach to treatment revolves around managing symptoms. Some medications are used to address specific symptoms. For example, selective serotonin reuptake inhibitors are prescribed to alleviate anxiety symptoms, considering that many patients show signs of anxiety. If there is a presence of acid reflux, acid suppression therapy may be prescribed. That’s why we are excited about the new medication because it is the first treatment for Rett Syndrome, targeting its underlying pathology.

Can you tell us more about this new treatment and what it means for the Rett community?

The new medication, called trofinetide, targets the specific pathway for the MECP2 gene mutation and works by reducing inflammation in the brain, stopping certain types of cells from becoming overactive, and increasing the amount of the naturally occurring protein called IGF-1.1

Since there are no specific laboratory tests or objective measurements available, the clinical trial relied on subjective information gathered through questionnaires from parents or caregivers. The results showed that parents or caregivers perceived a notable improvement in their child's presence and engagement.

For example, if the child that has some residual hand use, it could mean that they're better at grabbing things or feeding themselves. If the child uses a communication device, perhaps their responses on their device are more reliable. It could also mean that the child is making better eye contact or they're having fewer breath holding spells because they are less anxious, and their behavior is more regulated.

Overall, trofinetide has shown promising results in enhancing various aspects of a child's functioning and well-being in Rett syndrome.

How was UCSF involved with the early phase trials for trofinetide?

The former director, Dr. Mary Jones, was the Principal Investigator in the Phase 2 Rett syndrome study (Neu-2566-RETT-002), and UCSF served as one of the enrollment sites during the study from 2016-17. Dr. Jones devoted much of her life to providing compassionate care for her patients and was deeply committed to pushing the boundaries of scientific knowledge and research for Rett syndrome. Her legacy is one that fills me with pride as I continue to uphold her vision.

How is this medication administered and how long is the treatment?

Trofinetide is a liquid medicine, given twice a day. It’s a modifying therapy, similar to treatments for diabetes or multiple sclerosis, where we're changing the way the disease works in their body. Without treatment, those changes would revert back to the status quo for the patients.

What’s on the horizon for Rett Syndrome research?

There are two active gene therapy trials in their early stages, each using slightly different therapeutic approaches for targeting the MECP2 gene.

The pre-clinical data for these trials is encouraging and positive, but it is important to test the technique in humans to ensure its efficacy. Initially, these trials involve a very small number of participants, and the progress will be closely monitored for several years before expansion.

However, we are excited about the progress because a decade ago, we did not have such opportunities.

The uniqueness of the MECP2 gene lies in its deficiency in Rett Syndrome, while an opposite condition called MECP2 duplication syndrome reveals the devastating effects of excess gene expression. Developing a gene therapy requires a sophisticated approach to ensure that the gene is delivered to cells without causing overexpression, which could be equally detrimental.

What is different about treatment for Rett syndrome at UCSF Benioff Children’s Hospital?

At UCSF Benioff Children's, we pride ourselves on being a community-based hospital that integrates exceptional academic and research capabilities. Recognized as a Center of Excellence for Rett Syndrome, we’re one of the few centers in the US to offer multidisciplinary care for patients with Rett syndrome.

We provide wraparound care from head to toe, ensuring that our patients receive the utmost expertise, dedication, and support from our team.

We advocate to ensure that patients have access to vital resources, including physical therapy and all the necessary services they deserve. We firmly believe in the incredible potential of these patients and understand that they thrive within an enriched environment.

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