A Historic Step Forward: IDefine Approves $300,000 for Natural History Study with Boston Children’s Hospital

The Kleefstra syndrome (KS) community is celebrating a significant milestone in the journey toward clinical trial readiness, as IDefine’s Board of Directors has officially approved a $300,000 investment over three years to support a natural history study in partnership with Boston Children’s Hospital. This crucial funding covers half of the study’s total cost, with Boston Children’s Hospital providing the remaining funds, marking a collaborative partnership to drive forward research and therapeutic development for KS and other rare neurodevelopmental disorders (NDDs).

The study, part of the Accelerating Clinical Trial Readiness Innovations for Monogenic Neurodevelopmental Disorders (ACTION) Initiative, is a longitudinal natural history protocol designed to lay the foundation for future clinical trials. The primary goal is to determine appropriate endpoints and explore possible biomarkers. These will be essential for assessing the effectiveness of potential treatments in a future trial.

With the approval of the ACTION protocol by Boston Children’s Hospital’s Institutional Review Board (IRB), the study is now set in motion. A dedicated Clinical Trial Readiness Fellow has been hired and trained, and a team of researchers and physicians has been assembled under the Rosamund Stone Zander Translational Neuroscience Center. The center is a multidisciplinary collaboration of scientists and clinicians focused on developing targeted therapeutics for NDDs like Kleefstra syndrome.

The Importance of a Natural History Study for KS

For rare disease communities, securing therapeutic options is a long and challenging process. One of the key hurdles in advancing treatments is ensuring clinical trial readiness, which requires a thorough understanding of how a disorder progresses over time.

Eric Scheeff, PhD, IDefine’s Chief Scientific Officer, emphasized the importance of this study, saying, “As we’ve spoken with drug companies and researchers, we’ve consistently heard that clinical trial readiness is a critical factor in determining which disorders receive focus. If a condition is ready for a clinical trial, it significantly reduces the risk for pharmaceutical companies and researchers. This study ensures that when a promising treatment lead becomes available, we will be prepared to move forward more rapidly.”

The ACTION study will collect clinical data from 30 individuals with KS over three years, tracking their progression through standardized assessments. This data will serve multiple purposes:

• Establishing a baseline understanding of how KS progresses
• Acting as a potential control group for future clinical trials
• Identifying key windows of opportunity when treatments may be most effective
• Exploring endpoints to measure the success of therapies in clinical trials

Without these critical pieces in place, any promising treatment could be delayed, potentially leaving families in a difficult position where a candidate therapy exists, but cannot yet be properly tested.

“The worst-case scenario would be discovering an potential treatment and realizing we’re not ready to test it in a trial,” Scheeff said. “This study helps prevent that from happening.”

How the ACTION Study Works

The ACTION Initiative provides a standardized framework for data collection, which can be tailored to the needs of each specific disorder. For KS, experts including Dr. Siddharth Srivastava and Zoë Frazier, in collaboration with IDefine’s leadership, have carefully designed the study’s structure.

Participants with a confirmed molecular diagnosis of KS a deletion impacting 9q34.3 including EHMT1 or a pathogenic EHMT1 variant) are eligible for the study. Each participant will undergo annual evaluations for three years, which include:

• Family Interviews: Collecting detailed information on medical history and daily life
• Physical and Neurological Exams: Assessing motor skills, reflexes, and overall health
• Medical Record Reviews: Analyzing past clinical data
• KS-Specific Neurobehavioral Battery: Measuring cognitive and behavioral development
• Research EEGs and Fitbit Actigraphy: Monitoring brain activity and movement patterns
• Biological Sample Collection: Including blood draws for biomarker analysis
• Optional Photograph Collection: Documenting physical characteristics over time

A Strong Partnership for a Brighter Future

One of the most promising aspects of this initiative is the synergy between Boston Children’s Hospital and IDefine’s Kleefstra Syndrome Clinic. Many families who already visit the clinic for care will have the opportunity to combine their routine medical visits with participation in the natural history study, streamlining the process.

Scheeff underscored the strength of this partnership, stating, “Our collaboration with Boston Children’s Hospital has been incredibly productive. The level of expertise and support we’ve received gives us confidence that this study is in the best hands. It’s not just about sharing costs—it’s about working together in the most effective way possible to drive research forward.”

The Role of the KS Community

This study’s success relies heavily on the participation and dedication of the KS community. Families will need to commit to attending scheduled visits and completing assessments as required. While this commitment can be challenging, it is a vital step toward making future treatments a reality.

“Everything we’ve accomplished has been thanks to the KS community,” said IDefine CEO Geoff Rhyne. “But this study, perhaps more than anything, will depend on families stepping up and being involved. We need participants to show up, year after year, to ensure we collect the necessary data. It’s a lot to ask, but it’s how we move forward together.”

Looking Ahead

The approval and funding of this natural history study mark a major leap forward in the journey toward effective treatments for Kleefstra syndrome. By addressing critical gaps in knowledge and trial readiness, the ACTION study positions the KS community at the forefront of rare disease research.

Through collaboration, dedication, and the unwavering support of the IDefine community, the goal of developing targeted therapeutics for KS is now closer than ever. For families interested in participating in the ACTION study, more details on eligibility and enrollment will be provided in the coming weeks.