New Platform Targets and Represses Disease-Causing Genes

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Genes provide the most basic blueprint for building and regulating cell development, but as we age, these blueprints can get altered. As genes overexpress, they can cause a host of diseases, including neurodegenerative diseases like Alzheimer’s and Parkinson’s.

A new platform developed by Ornit Chiba-Falek, PhD, professor in neurology, and Boris Kantor, PhD, research professor of neurobiology, could help slow down these overexpressed genes and provide safer, more precise therapeutic approaches for a host of diseases.

The platform uses adeno-associated virus (AAV) vectors, which work like delivery trucks carrying cargo to genes. CRISPR tools are the cargo of choice, but they are bulky, and AAVs are small, so their packaging capacity is limited.

“One the one hand, you have this delivery vehicle that is highly efficient, highly safe, and extremely popular, but difficult to combine with CRISPR because of the size,” Kantor said. “Our idea was to bridge between the two and create an all-in-one system.”

Using CRISPR with a deactivated Cas9, a tool that works as a GPS system to bind guide RNA to the target of interest, Kantor and Chiba-Falek developed an epigenome editing approach to repress the genes that gain a toxic function that allows them to overexpress and cause disease. For neurodegenerative diseases, this platform targeted the APOE gene.

The system was validated both in the lab and in mouse models and showed over an 80% repression of the target gene. In a mouse model, it was tested in the hippocampus and targeted the APOE gene. The system demonstrated sustained repression over time, indicating its potential for long-term therapeutic benefits.

“If we completely eliminate the APOE gene,” Chiba-Falek said, “other issues can form, but using our system, we can fine-tune the expression of the APOE gene.” This means that the APOE gene can still be expressed, but only in a way where it can maintain function of the brain cells without the negative effects that form because of overexpression.

And because this method fine-tunes the expression of genes, it could work for people with different genetic backgrounds that cause Alzheimer’s and Parkinson’s disease. “There is no silver bullet in these diseases,” Chiba-Falek said. “Alzheimer’s is not a single disease. Parkinson’s is not a single disease. By targeting specific genes, we are offering a therapeutic approach for progressing or promoting precision medicine for these diseases. It’s not the same therapy for all patients.”

In contrast to traditional drug treatments, gene therapy products usually only require one treatment and can typically affect the disease course in the long term and in a sustained way. Their platform is designed to target specific genetic locations associated with a variety of neurodegenerative diseases and disorders.

The success of this all-in-one AAV system could significantly advance gene therapy and offer a safer, more efficient, and precise way to treat a variety of genetic and neurodegenerative disorders.


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