A novel SHANK3 minigene for gene therapy approaches

Phelan-McDermid Syndrome (PMS) is a rare genetic condition that affects brain development and is often caused by a missing or non-working copy of a gene called SHANK3. This gene plays a vital role in how brain cells (neurons) communicate with each other, especially at points where they connect, called synapses. Current efforts to treat PMS using gene therapy are already in clinical trials, using shortened versions of the SHANK3 gene (called minigenes) that can be delivered to the brain. However, these versions are incomplete—they are missing important sections known as proline-rich (P-rich) regions. Recent research from our group has shown that these missing pieces are likely critical for SHANK3 to form connections with other proteins. In this project, we aim to develop a new, improved version of the SHANK3 minigene, called SHANK3-PP, which includes the P-rich regions. We will test how well this new gene works in lab-grown neurons made from stem cells taken from a person with PMS. We will measure how these neurons function and how well they form connections using advanced techniques, including high-resolution imaging and electrical recordings. Finally, we will test whether this improved gene can be safely delivered to the brain in mice using the same type of gene therapy approach used in clinical trials. If successful, this work could lead to better gene therapy options for people with PMS by restoring more of the SHANK3 gene's natural function.