This project, led by Prof Karen Anthony at the University of Northampton and Dr Ronald Buijsen at Leiden University Medical Centre, aimed to evaluate the potential of targeting RNA to treat Spinocerebellar ataxia type 1 (SCA1) using a type of gene therapy called SMaRT.
SCA1 is caused by a change in the Ataxin 1 gene leading to a toxic form of the Ataxin 1 protein being made. The researchers investigated whether a type of gene therapy called SMaRT (spliceosome-mediated RNA trans-splicing) could convert the toxic form of Ataxin 1 into a non-toxic healthy form as a potential treatment for SCA1.
To do this, they took cells from people with SCA1 and converted them back into pluripotent stem cells that can transform into any type of cell. They then turned these into neurons, which are the types of cells affected in the brain of people with SCA1. In cells, a molecule called messenger RNA (mRNA) contains the instructions for making a protein. This makes the mRNA a good target for treating conditions like ataxias, because editing the mRNA can stop a mutated version of a protein being formed, or reduce the amount that is.
Using a virus that is harmless to cells as a vehicle, the researchers delivered a molecule to alter the mRNA in the neurons through a process called splicing (essentially editing RNA by cutting out unwanted parts), leading to it forming at healthy version of the Ataxin 1 protein. They were able to successfully do this, and were able to replicate this in a mouse model of S
CA1 too.
Following on from this project, the researchers are carrying out work to look at the functional effects of SMaRT therapy in SCA1 cell and mouse models, such as the aggregation of proteins in cells. They hope that the therapy will provide benefit not only to people with SCA1, but also in other types of spinocerebellar ataxias.
This research was presented with a poster at ICAR 2024 (pictured left). The researchers are currently working on a publication to share results from the work carried out following the Ataxia UK-funded project, which we will share with the community in 2026.
