On 6/29/22, the HOPE for Harvey Foundation signed a contract with Everlum Bio, a rare disease lab who believes that everyone deserves a cure, no matter how big or small the disease. Everlum Bio is based in Austin, TX, and we are excited to partner with them on creating a treatment for DLG4-related Synaptopathy, focusing on ASOs and small molecule screening. Through this relationship and in collaboration with iXcells, HOPE for Harvey successfully derived 6 induced pluripotent stem cell (iPSC) lines for DLG4 and designed some potential ASO candidates. Due to limited binding potential at this time for Harvey's specific binding locations for ASOs, this work has been paused as we complete more research to better understand the impacts of Harvey's specific mutation and differences from other DLG4 mutations.
On 3/16/23, HOPE for Harvey signed an additional contract with Hebrew University of Jerusalem and Rami Aqeilan's lab in collaboration with the SHINE Foundation to support the research and development of a virus-based gene replacement therapy called an AAV. Dr. Aqeilan's lab has successfully identified an AAV and has developed neuronal lines and brain organiods (3D neurons) of various DLG4 mutations. They are now working on grant funding to continue testing their AAV for DLG4.
In the summer of 2023, the HOPE for Harvey Foundation applied for two DLG4 animal model grants at Jackson Laboratories (Jax) and the Center for Precision Animal Modeling (C-PAM) at the University of Alabama at Birmingham (UAB), and both were accepted and are currently in progress. After a failed attempt in December 2023, Jax re-engineered their mouse model carrying Harvey's specific missense mutation, and had their first pups born in May 2024. Jax was able to identify male mice carrying the transgene in August 2024 and are now attempting to breed colonies of these mice. We hope to be ready to send these mice out to labs to test various gene therapy approaches in the coming months.
In the spring of 2024, HOPE for Harvey began working with NeuCyte on generating iNeurons from the iPSC cell lines in order to test treatments and better understand how different variants function across dominant-negative/GoF and haploinsufficient patients. NeuCyte successfully derived GoF neurons and a small batch of healthy, wild-type (WT) neurons. NeuCyte is now building out more neuronal controls, including a haploinsufficient line and has begun testing these neurons. Using multi-electrode arrays (MEAs), NeuCyte has observed differences between the mutated and healthy neurons. In addition, NeuCyte has run RNAsequencing on Harvey's mutant neurons compared to healthy neurons and has identified differences in related proteins. We hope to use AI technology to narrow our target list from all of the potential targets identified. One we have all of the neuronal lines, NeuCyte will run several tests, including more MEA data; protein-specific assays such as Co-IP experiments to determine mutant versus healthy protein function for DLG4 and other impacted proteins; and various assays such as SiRNA designs to look at what 'knocking down' the mutant copy would do to the mutant neurons compared to the healthy neurons. Once these tests are completed, we hope to run various readily available drugs to see if we can alter the behavior of the mutant neurons to make them behave like the healthy neurons.
We are currently working on these specific pre-clinical development tasks with funds from our GoFundMe/GiveButter Campaigns and HOPE for Harvey Foundation Fundraising Efforts with the following estimated costs:
Current Total Costs: ~$390,000
Additional anticipated Pre-Clinical Development Costs: TBD for above listed
HOPE for Harvey is currently exploring various grant opportunities as well to help offset these and future research expenses
Check-out this video from our AAV project with Rami Aqeilan, Hebrew University of Jerusalem
Currently there are no treatment options for DLG4-related Synaptopathy. We hope to change that with your help! 100% of donations will support the development of various treatment modalities.
Due to advocacy by HOPE for Harvey Foundation, four additional academic labs recently started research projects on DLG4-related Synaptopathy:
"Collins concluded by thanking his audience while urging them to do more. 'Of nearly 7,000 genetic disorders, only 500–600 have an FDA-approved therapy,' he said. The goal is to develop therapies for the thousands of disorders for which patients and their families are still waiting in vain."
"After excluding genetic variants that were also found in the control group and in a separate large cohort of more than 60,000 individuals without autism, Doan, Yu and colleagues were left with 41 genes that were knocked out only in individuals with autism. Overall, the researchers estimate that these genes explain another 3 to 5 percent of all cases of autism (2 percent from loss-of-function mutations, and 1 to 3 percent from missense mutations)."
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