K.I.D.S. IQ Project is currently funding three projects related to Kleefstra Syndrome. Each project leverages a different type of drug screen approach, with the ultimate goal of each being to identify potential drug candidate that can be refined further (for eventual testing in human Kleefstra Syndrome patients). In addition, we have designed our projects such that the learnings and findings from each drug screen can be applied to numerous other Intellectual Disability disorders. Please see below for a more detailed description of the three projects in the process of being funded.

Kleefstra Syndrome: Focused Drug Screen on Human iPSC-derived Neurons and Subsequent Mouse Testing of Lead Compounds

This project formally began in December 2016 and is being led by Dr. Hans van Bokhoven and Dr. Nael Nadif Kasri, both of Radboud University (The Netherlands), in collaboration with Dr. Hans Bjornsson of Johns Hopkins University in the United States. The leaders of this research team have completed a screen of a short list of chemical compounds (drugs). They leveraged drugs that have historically been able to target syndromes and diseases which are similar to Kleefstra Syndrome, and other drugs well-suited to address the biology of Kleefstra Syndrome itself.

How exactly did this screen work? The Radboud team had previously developed Kleefstra Syndrome neurons (brain cells), derived from a patient’s skin sample, through an innovative process involving induced pluripotent stem cell (iPSC) technology. These neurons resided in a petri dish and were evaluated for deficiencies as compared to neurons from a healthy patient. The team began testing the impact of the selected chemical compounds to assess their ability to improve noted deficiencies. After the initial screen of the compounds, the team identified one particular compound which showed significant promise in improving neuronal deficiencies. To our knowledge, this is the first time in history that a specific compound has been shown to improve or reverse Kleefstra Syndrome in a lab environment, in any kind of human or animal model. However, it is important to keep in mind that drug development is a complex and involved process, and this progress will require significant follow-up testing and validation over a multi-year period.
Pending approval from our Scientific Advisory Board, the research team will advance the compound to mouse testing in order to better understand the behavioural and cognitive impacts. This next phase of the project is expected to last up to two and a half years, with a goal of identifying a potential drug candidate for testing on human Kleefstra Syndrome patients.

Screening Potential Drugs To Upregulate EHMT1 (Kleefstra Syndrome Gene)

Our second project is underway and is being led by Dr. Carl Ernst of McGill University and Douglas Hospital Research Institute in Canada. Dr. Ernst is in the process of creating neuronal cells from a Kleefstra Syndrome patient’s skin sample to be used as a screening tool for chemical compounds, also leveraging iPSC technology. The screen will look for drugs that specifically increase the production of the EHMT1 protein, which is insufficiently produced in Kleefstra Syndrome patients.

Why might this overall approach work? Like all humans, Kleefstra Syndrome patients are supposed to have two healthy copies of EHMT1. However, these patients’ gene mutations or deletions result in one copy being deficient. In identifying drugs that can successfully interact with, and stimulate increased production of EHMT1, we may be able to produce enough of the protein to compensate for the deficiency. This approach is known as “upregulation” and has proven successful in other diseases with similar challenges. Dr. Ernst will begin his work screening FDA-approved drugs and, given these drugs have already passed many hurdles, any early success may result in tremendous time and cost savings. This project is in its early phases and is expected to last up to two years from launch, with a goal of identifying a potential drug candidate for testing on human Kleefstra Syndrome patients.

Kleefstra Syndrome: Broad-Based Drug Screen on Human iPSC-derived Neurons

This project is being led initially by Dr. Carl Ernst of McGill University in Canada, followed by phase-two leadership from Dr. Yi Zhang of Boston Children’s Hospital (BCH) in the United States. The BCH team will convert iPS cells (created by Dr. Ernst) to neuronal cells for detailed study. The neuronal cells (and their associated phenotype) will then be used in a broad-based drug screen covering hundreds of thousands of existing drugs and other non-commercialized compounds. This project is in phase one and is expected to last up to three years, with a goal of identifying a potential drug candidate for testing on human Kleefstra Syndrome patients.

Message to Researchers

If you are a researcher currently engaged in or potentially interested in translational scientific research in our areas of interest, please contact us. We note that some of the research tools we are currently developing (such as an iPSC bank) are being made available to the research community more broadly and, as such, this can significantly reduce the time and cost associated with future research projects you may be contemplating. Contact us

Message to Families

In order to facilitate our funded research projects requiring patient participation or samples, K.I.D.S. IQ Project may rely on a given research team’s existing access to such patients and samples; alternatively and depending on the nature of the research, K.I.D.S. IQ Project may also independently contact and recruit select families that have provided contact details on our Basic Contact Form. Whether patients/samples are recruited through K.I.D.S. IQ Project or readily accessible through an existing research team, K.I.D.S. IQ Project generally aims to utilize patients (or groups of patients) that collectively represent the broadest cross-section of the patient population. However, the specific selection criteria may vary by project depending on the scope of the project itself. Additionally, careful consideration during the recruitment and selection phase is given to scientific methodology and design – for example, in certain studies, a same-sex sibling control within a certain age differential may be necessary to proceed with a given set of experiments. In order to protect the privacy of patients, K.I.D.S. IQ Project does not disclose the names of any patients participating in any of our funded or sponsored research – see our Privacy Policy for additional details with respect to additional privacy matters.