Funding outcome

Spinal muscular atrophy (SMA) is a severe inherited disease that affects infants and young children, causing progressive muscle weakness and difficulty breathing. SMA occurs when the body lacks a critical protein, called survival motor neuron (SMN), which is required for healthy nerve and muscle function. Several treatments for SMA have been approved, including gene therapy and antisense oligonucleotides (ASOs). ASOs are small DNA-like molecules that help cells produce SMN protein. While these therapies have improved survival, they do not work well for all patients, often lose effectiveness over time, and can cause serious side effects. ASO treatments also require repeated injections into the spinal fluid, which are invasive and stressful for children. A major challenge is delivering ASOs efficiently to all affected tissues. SMA is now known to be a multi-organ disease that affects the muscle, heart, and immune tissues in addition to the nervous system. Current treatments primarily target the brain and spinal cord, leaving other organs insufficiently treated. My research addresses this problem using DG9, a chain of amino acids called a peptide that acts as a delivery helper. DG9 helps ASOs enter cells more effectively and allows them to reach tissues throughout the body after a simple injection under the skin. Previous work has shown that DG9-delivered ASOs improve survival and muscle function in severe SMA mouse models. The aim of this project is to identify the most effective and safest version of DG9. I will test eight DG9 variants with changes in size and charge to determine how these features affect ASO delivery, SMN restoration, tissue distribution, and therapeutic benefit in SMA mouse models. I expect to identify an optimized DG9 variant that enables safer, less invasive, and effective whole-body treatment. This work has the potential to greatly improve the quality of life for children with SMA and support the development of therapies for genetic diseases.