Updates from the Director of Scientific & Clinical Initiatives
July 2025
Last week, The Dup15q Alliance sponsored both a Scientific Symposium and Family Conference in Indianapolis! The event was well-received from scientists and families alike, with already well-informed individuals learning so much more about what is going on in the world of Dup15q syndrome. At the Scientific Symposium, I co-moderated 33 talks from Dup15q and Angelman syndrome researchers that helped our scientists learn from each other and foster partnerships going forward. At the Family Conference, families found community with others who understand their experiences and learned practical tips about what to expect as their loved ones with Dup15q grow up. We highlighted some of the ongoing scientific research and our hope for therapeutic breakthroughs in the coming years for our loved ones. An overview of the talks from both the Scientific Symposium and Family Conference will be released separately. -Dylan Ritter
LEARN
New Paper on Dup15q Syndrome:
Earlier this month, a collaborative study was published that sought to identify some of the underlying mechanisms that could explain differences in Dup15q vs. non-Dup15q brains. This work would not have been possible without the generous donations that families in the Dup15q community have made to Autism BrainNet.
The research study compared control and Dup15q post-mortem brain tissue and brain organoids (mini brains in a dish grown from patient stem cells). Within each sample, the researchers sequenced RNA, the molecule synthesized from reading your DNA that tells the cell which proteins are needed to perform a specific function (more about this in the CURE section). It is important to note that changes in RNA DO NOT ALWAYS EQUAL changes in protein that affect biology. The conclusions drawn in this study highlight important ideas to study, but these ideas may not be a full explanation of what is happening in Dup15q brain cells.
Briefly, this study found that:
- Gene expression changes inside and outside the 15q11.2-13.1 region were observed in Dup15q vs control. They found changes in transcription factor RNA, which could theoretically lead to some widespread changes in cell function.
- Issues in energy production and neuron outgrowth are suggested to be affected in Dup15q neurons from RNA data. Transplanting Dup15q neurons into mice demonstrated reduced neuron outgrowth.
- There are similar gene expression changes between Dup15q samples (who had ASD) and other genes implicated in ASD.
- Gene expression changes varied depending on what cell type or brain region you looked at. In a subset of neurons, energy production and neuron outgrowth appear to be affected in the Dup15q samples.
Takeaway: This paper generated a wealth of data for other researchers to follow up in their own studies. Findings that energy production and neuron growth could be implicated in Dup15q syndrome support current literature of changes in Dup15q neuron structure and function. Future studies are needed to validate individual genetic or cellular process contributions to Dup15q neuron function.
We at the Dup15q Alliance caution the use of AI technologies to summarize scientific research papers. There has been substantial evidence of inaccuracies or falsifications in these summaries, so please take AI-generated summaries with a grain of salt. We will work at the Alliance to generate lay summaries of new Dup15q papers for the accurate dissemination of scientific findings. A detailed summary of this paper can be found on our website.
TREAT
Anti-Seizure Clinical Trial
At the conference, we heard a presentation from a board member and current Lundbeck employee, Sophia Cacciatore, describing an ongoing phase 3 clinical trial for an anti-epileptic drug called bexicaserin. Bexicaserin binds to serotonin receptors to reduce seizures in the context of developmental epileptic encephalopathies. Results from phase 2 were positive, showing an overall decrease in countable motor seizure frequency of 58% across 40 participants.
The rationale behind the clinical trial design is that serotonin receptors could be a way to treat seizures in developmental epileptic encephalopathies, regardless of the genetic underpinnings of the seizures. As such, Lundbeck is enrolling patients from a wide range of rare neurodevelopmental disorders with epilepsy in the DEEp OCEAN study if individuals meet the inclusion criteria. You can learn more about the study, actively enrolling sites, and inclusion criteria to participate by visiting the DEEp OCEAN website!
CURE
Targeting mRNA with ASOs
In a cell, there are three main targets for therapeutics: DNA, messenger RNA (mRNA), and protein. DNA holds the information for making all proteins that a cell could possibly need to function. You can imagine DNA as the family cookbook of the cell that has been passed down through generations, holding all the recipes needed to make any signature dish. To make a dish from a very old and precious cookbook, you may choose to write down the recipe on a recipe card so that you don’t run the risk of damaging the cookbook in the kitchen. In a cell, the DNA is so precious, that cells “write down” the pertinent information needed in a molecule called mRNA that looks very similar to DNA. It has sequences of letters that can be read like a code to tell the cell the instructions needed to make a specific product! The code tells the cell what amino acids (ingredients) need to be combined in the correct order to make a final product. This final product, called a protein, is akin to a dish prepared from the recipe card transcribed from your family cookbook.
Therapeutics often target one of these three molecules in the cell (DNA, mRNA, or protein). DNA is targeted with technologies like CRISPR. CRISPR is being employed in some diseases, but current DNA-targeting technologies have too many limitations to be used efficiently in central nervous system disorders like Dup15q. Proteins are therapeutically targeted using small molecules, a treatment category that includes almost all medications you take at home. However, the UBE3A protein (likely responsible for many Dup15q symptoms) has been very difficult to target using a small molecule approach. Luckily for researchers, the mRNA for UBE3A can be regulated using an ASO. By designing an ASO specific to the UBE3A mRNA, researchers can decrease levels of UBE3A mRNA (and ensure that decreases levels of UBE3A protein) in cells. Current work by our therapeutic partners at Kicho and Quiver is testing UBE3A ASOs to reduce levels of UBE3A protein in animals without any toxic side effects. One day, we hope to see UBE3A ASOs available in the clinic as a first therapeutic option to treat the underlying cause of Dup15q syndrome!
