Well, gene therapy, it’s quite an innovative approach to treat more than genetic diseases and more complex diseases, such as related to age common diseases, such as Alzheimer’s, Parkinson’s, dementia, and others, so this approach is really innovative and an advantage of this approach is usually it’s one shot, one treatment, which is huge because you really take care of the root of the disease, genetic root, and you supply a genetic cargo which can potentially fix the disease...
Well, gene therapy, it’s quite an innovative approach to treat more than genetic diseases and more complex diseases, such as related to age common diseases, such as Alzheimer’s, Parkinson’s, dementia, and others, so this approach is really innovative and an advantage of this approach is usually it’s one shot, one treatment, which is huge because you really take care of the root of the disease, genetic root, and you supply a genetic cargo which can potentially fix the disease. Again, as I mentioned, one shot, one treatment. So related to Alzheimer’s disease, there are multiple approaches based on gene therapy which we involve, but I would like to discuss here our main approach, which is based on epigenome editing of genes involved in Alzheimer’s disease and specifically a gene called ApoE isoform E4. So epigenome editing approach, it’s sort of branching out of a conventional CRISPR-Cas-based approach, which some people call repurposing, because immediately after CRISPR-Cas appears as a revolutionary technology based on Active Cas9 and other components of this system, immediately after the discovery, which was a little bit more than a decade ago, a purpose of this system led to development of epigenome editing technologies, which are very actively utilized to model gene expression of genes involved in pathologies related to Alzheimer’s disease, Parkinson’s disease, and other neurological diseases. So how does this system work? It’s still the same CRISPR-Cas system, which is recruited to the locus or gene of interest. In this case, we’re talking about ApoE4 isoform, a gene at highest risk for Alzheimer’s disease, as many know in the field, carrying just one allele of ApoE4 increases your risk to develop Alzheimer’s disease twice. And being homozygous for APOE4, meaning carrying two alleles of the defective gene, will increase your chance to develop Alzheimer’s disease by a factor of close to 20. So it’s very penetrative. It’s almost like a mutation. And the difference between APOE4 and the other isoforms is just a single nucleotide polymorphism, a single change in amino acid and related base pair. So the epigenome editing approach is based on the ability of CRISPR-Cas to see this small change in nucleotide and in a very specific and accurate way bind this SNP or bind this nucleotide. So the idea is we really want to target APOE4 and the system can allow us to target APOE4 specifically without targeting any other isoforms. We don’t want to target APOE2, which is protective. We don’t want to target APOE3 in this case. We want to develop what we call an allele discrimination approach. So we want to target specifically APOE4, and the CRISPR-Cas system can allow us to do that. So if CRISPR, and specifically the Cas9 component, can be linked to an epigenome factor, and we developed a system called an epigenome editing system based on Cas9 and effector molecule, which is a repressor. To be more specific, it’s based on KRAB, which is a general repressor, linked to MECP2 repressor. So this is a part of the system which we develop in our lab. So if the system can be specifically bound to that isoform of APOE4 and modulate expression, and by means of modulation, we mean repress that gene, so to downregulate expression of APOE4 specifically in a lead discrimination mode, then the goal is achieved, and we can repress APOE4 specifically without targeting any other components of the APOE gene and potentially lead to a cure of late-onset Alzheimer’s disease.
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