Written by Dr. Marija Cvetanovic Edited by Dr. Sriram Jayabal
Research group in Michigan report the creation of the first NIH-approved human cell model that mirrors SCA3 disease features – cellular defects that, after gene therapy, show improvement
Spinocerebellar ataxia type 3 (SCA3) is a dominantly-inherited, late onset genetic disease that affects multiple brain regions. Affected individuals suffer from several symptoms, with impaired movement coordination being the most debilitating. SCA3 is caused by a mutation in the Ataxin-3 (ATXN3) gene. In unaffected individuals, ATXN3 typically has anywhere from 12 to 44 repeats of the genetic code “CAG;” however, in some people’s genetic code, the number of CAG repeats can become abnormally high. If this “repeat expansion” mutation causes the ATXN3 gene to have more than 56 CAG repeats, the person develops SCA3. Cells use repeating CAG sequences in their genome to make proteins with long tracts of the amino acid glutamine. In SCA3 cells, these “polyglutamine” (polyQ) tracts are abnormally long in the ATXN3 protein, which makes the protein more prone to form clumps (or “aggregates”) in the cell. The presence of these protein clumps in the cells of the brain is one of the hallmarks of SCA3.
Despite knowing the genetic cause of SCA3, it is still not known how this mutation affects cells on the molecular level. Having said that, several cellular and animal models have been developed in the past two decades to help study these underlying mechanisms. SCA3 models have not only helped to our increased understanding of the disease’s progression at all levels – molecular, cellular, tissue, and behavioral – but also helped move us closer to therapeutic interventions. For instance, recent studies using SCA3 mouse models have established that targeting ATXN3 with a form of gene therapy known as antisense oligonucleotide (ASO) treatment could very well be an effective strategy for improving the lives of patients. ATXN3-targeting ASOs cause the cells of the brain to produce less of the mutant ATXN3 protein and, when given to SCA3 mice, improved their motor function. These results strongly support the potential use of ASOs to treat SCA3. Still, it is important to see if this finding can be repeated in human neurons (a step that is needed to bring us closer to ASO clinical trials).
Previous experience from unsuccessful clinical trials highlight the importance of determining the similarities and differences between humans and mice when it comes to disease. For instance, the SCA3 mutation does not naturally occur in mice; therefore, modeling SCA3 with mice usually requires additional genetic manipulation, which could lead to unexpected effects that we do not typically see in patients. In addition, we may miss important determinants of SCA3 pathology due to the inherent differences between humans and mice. For example, proteins that help contribute to SCA3 in human patients may simply not be present in mouse neurons (and vice versa). Because of such species differences, the therapeutic interventions that are effective in mice are not always as effective in humans.
SCA3 human neurons can help bridge the gap between rodent models and human patients, acting as a clinically relevant tool for looking into disease mechanisms and testing new therapies. Because we cannot remove a portion of an SCA3 patient’s brain to study the disease, these neurons must be created in a lab. Human neurons can be generated from induced pluripotent stem cells (iPSCs) or from human embryonic stem cells (hESCs). Induced pluripotent stem cells (iPSCs) are made from adult cells (usually blood or skin cells) that are reprogrammed to return to an embryo-like form (known as the “pluripotent” state). Just like during normal development, iPSCs can create many different types of cells, including neurons. One problem with this approach is that the process of reprograming can potentially change these cells in way that could affect how the disease presents. To avoid this issue, researchers can also create human neurons from human embryonic stem cells (hESCs), which are derived from embryos and are, therefore, naturally pluripotent. Because hESCs do not require reprograming, they are more likely to accurately model disease. However, they are more difficult to obtain and work with. The researchers in this study, led by Lauren Moore in Dr. Hank Paulson’s lab at the University of Michigan, used hESCs to generate the first ever National Institutes of Health (NIH)-approved SCA3 model using human cells.