Kleefstra Syndrome Drug Development Research Fund

K.I.D.S. IQ Project is now funding three distinct research projects, all approved by our Scientific Advisory Board in 2016 and described in detail below. Our progress to date would not be possible without our donors. All funds raised specifically through GlobalGiving Foundation have been applied to a portion of the funding requirement for the second project below. Once again, we thank you for your continued support!

Project 1: Kleefstra Syndrome - Focused Drug Screen on Human iPSC-derived Neurons and Subsequent Mouse Testing of Lead Compounds

Our first 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.

Project 2: Screening Potential Drugs To Upregulate EHMT1 (Kleefstra Syndrome Gene)

Our second project is also 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.

Project 3: Kleefstra Syndrome: Broad-Based Drug Screen on Human iPSC-derived Neurons

Our third 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.

Links:

• https://www.kidsIQproject.org

In 2015, K.I.D.S. IQ Project began raising money to fund scientific research projects aimed at advancing a drug treatment for Kleefstra Syndrome (KS). With the help of our partner organization, GlobalGiving Foundation, we made great progress toward our funding target and have now raised approximately C$762,000 globally. Based on recommendations of our Scientific Advisory Board (SAB), K.I.D.S. IQ Project made the decision to deploy some of these funds on various research projects.

The first 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 assembled and are beginning to screen a short list of chemical compounds, leveraging those that have historically been able to target syndromes and diseases that are similar to Kleefstra Syndrome (or those that may be best suited to tackle what is already known about the biology of Kleefstra Syndrome itself). How exactly will this screen work? The Radboud team has developed Kleefstra Syndrome neurons (brain cells) in a lab, with these neurons having been derived from a patient’s skin sample through a process involving induced pluripotent stem cell (iPSC) technology (iPSCs are a relatively new technology that enable neurons to be derived from disease patients). These disease-state neurons have been evaluated for deficiencies as compared to normal neurons, and the team will be able to test the impact of chemical compounds in terms of their ability to improve noted deficiencies. After an initial screen of the compounds, the team will advance the top candidates (which produce the most significant improvements) to test in Kleefstra Syndrome mice. Mice are an important part of the testing as they provide are a read on behavioral and intellectual changes. This project is expected to last up to three years, with a goal of identifying a potential drug candidate for testing on human Kleefstra Syndrome patients.

A second project was funded in January 2016 and is being led by Dr. Carl Ernst of McGill University in Canada. Dr. Ernst is in the process of creating neuronal or similar cells from a Kleefstra Syndrome patient’s skin sample that can be used as a screening tool for chemical compounds, also leveraging iPSC technology. The tool will screen for drugs that specifically increase the production of the key protein (EHMT1) implicated in Kleefstra Syndrome, as this protein is not produced in sufficient quantity in Kleefstra Syndrome patients. Why might this overall approach work? Kleefstra Syndrome patients have two copies of EHMT1 (just like the normal human population), with one copy functioning normally and the other being deficient (that deficiency is caused by the patient’s deletion or mutation). In working to identify drugs that can successfully interact with and stimulate increased production of the healthy copy of EHMT1, we may be able to compensate for the lack of EHMT1 production stemming from the unhealthy copy. This overall approach, known as “upregulation”, has proven successful in other diseases where one copy of the mutated/deleted gene was originally not producing in sufficient quantity. Dr. Ernst will begin his work screening FDA-approved drugs and, given these drugs have already passed many hurdles, any early successes could result in tremendous time and cost savings. This project is expected to last up to two years, with a goal of identifying a potential drug candidate for testing on human Kleefstra Syndrome patients.

Our progress to date would not be possible without our donors. All funds raised specifically through GlobalGiving Foundation have been applied to a portion of the funding requirement for the second project described above. Once again, we thank you for your continued support!

Links:

• https://www.kidsIQproject.org