HEAT-Net 2021 | CRISPR–Cas9 gene therapy for neurodegenerative diseases

In our lab, we have been mainly interested in designing and evaluating different immunotherapies against pathological proteins in both Alzheimer’s disease and Parkinson’s disease. And while we are still working along those lines, we have also begun to evaluate gene editing for the same disorders. So we envision that by using CRISPR-Cas9 mediated allele disruption, we can hopefully, in the future, slow down or even stop the generation of excessive amounts of these proteins or the formation of particular disease-causing variants. And at this point, I think that the strategy would fit best for any of the dominantly inherited disease forms caused by mutations in a number of genes, but the approach could possibly also be extended to the vast majority of sporadic disease cases.

And we began to work on CRISPR-Cas9 some years ago, while I was on a sabbatical with Xandra Breakefield at Mass General Hospital in Boston, and with the help of Bence György, who was, at the time, a post-doc in Xandra’s group, and Camilla Lööv, who was post-doc with Brad Hyman at the time, we could show that by treating human fibroblasts that were carrying the so-called Swedish mutation in the APP gene, with CRISPR-Cas9 we could suppress the overproduction of Aβ that such cells otherwise display. And we were also able to show that the same approach could disrupt the overexpressed gene in primary neurons from the transgenic mice, as well as in the hippocampus of living such mice. So, that was our previous work.

So, more recently, my PhD student Evangelos Konstantinidis, he has, together with Agnieszka Molisak, who is a post-doc in the lab, they have worked on another gene, another mutation that is also causing familial Alzheimer’s disease. So, what they have shown is that they can target the mutated allele on patient fibroblasts very much similar to what we did on the fibroblasts with the Swedish mutations back with Xandra. So they could show that the mutation induced increase in the ratio between the more toxic and more aggregation-prone Aβ42 versus Aβ40, could be partially normalized with CRISPR-Cas9. And we have also studied some other aspects related to this mutation and seeing what effect that CRISPR-Cas9 has on those aspects.

So, I mean, we have also begun to target α-synuclein as an attempt to design the gene editing approach that would also allow us to, in the future, treat patients with Parkinson’s disease. And also there, we have started with a particular disease-causing mutation in the gene for α-synuclein. However, we have also started to use this technology in order to more generally suppress the expression of the wildtype allele of both APP and α-synuclein. So what we envision, although there is a lot of work to do here before we can know how to really do this, but is to suppress the expression of these genes in a way that is regulatable and that doesn’t suppress the expression all the way down to zero. So we believe that this could, if we learn how to do it, also be used in the future to treat the vast majority of patients who have sporadic disease.