Leiden University Medical Center Research: The Development of a Novel RNA Therapy and Innovative Delivery Methods for SCA1

This information is from https://sca1research.nl/en: "In this research we will investigate in the lab if we can prevent or lower the production of the harmful ataxin-1 protein. As in previous research, so-called antisense oligonucleotides (ASOs) are used for this. In each cell, a messenger molecule, the so-called mRNA, is made based on the genetic information in the DNA. This molecule is then 'read' to make proteins. The AONs attach themselves specifically to the mRNA of the ataxin-1 gene, causing it to be broken down. As a result, less, or even no, harmful protein is made. The expectation is that this treatment will limit the damage to the brain in SCA1 and thus slow the progression of the disease or alleviate the symptoms. If successful, this will mean a major step forward for people with SCA1. This study concerns the development of a completely new medicine. This is a careful and lengthy process that will take many years. The first phase of this project will investigate what the ataxin-1 gene looks like in people with SCA1 in the Netherlands. Everyone has small differences in their DNA that usually do not affect the functioning of a gene. These differences can help to target the AONs very precisely to the diseased gene, without affecting the healthy gene. The goal is to stop the production of the harmful protein, while the healthy protein continues to function. In this way, researchers hope to reduce the chance of side effects. The AONs will be tested in advanced stem cell models that were previously developed at the LUMC, where this part of the research will also take place. Currently, ASOs for brain diseases are usually administered via a spinal injection. This must be done in the hospital and the procedure is often experienced as painful by the patient. For this reason this project also investigates new methods of administration, in which ASOs can be administered less often and/or via the blood. These methods may make it possible for the ASOs to cross the blood-brain barrier and reach the brain without a spinal injection. The functionalized ASOs and the ASO nanoparticles are developed and tested at the UMCG. They will then be further tested at the LUMC."