Jennifer Martelle Tu, MD, PhD

The United States Food and Drug Administration (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. Jennifer Martelle 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 moments in a child’s 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, the child’s 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 when a health care provider suspects the possibility of Rett syndrome, usually with concerns about the child’s development when it plateaus, or they start to lose skills. There are several hallmark features that help doctors identify the 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, because many patients show signs of anxiety. If the patient has acid reflux, acid suppression therapy may be prescribed. That’s why we are so excited about the new medication: It is the first treatment for Rett Syndrome that actually targets its underlying pathology.

Rett Syndrome

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.  

Since there are no specific laboratory tests or objective measurements available, the clinical trial relied on subjective information gathered through questionnaires from parents and caregivers. The results showed that parents and 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 their ability to grab things or feed themselves improved. If the child uses a communication device, perhaps their responses on their device became 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.

Rett Syndrome

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.

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

The former director, Mary Jones, MD, was the principal investigator in the phase 2 Rett syndrome study, and UCSF served as one of the enrollment sites during the study from 2016 to 2017. 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. 

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. That said, we are really excited about this progress, because a decade ago, we didn’t have opportunities like this. 

What is different about how we treat Rett syndrome at UCSF Benioff Children’s Hospitals?  

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

What really sets us apart is that we provide wraparound care from head to toe, ensuring that our patients receive the absolute best when it comes to expertise, dedication, and support from our team. We also do a lot of advocacy, to  ensure that our 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.