Development of synthetic gene feedback circuits to prevent tau aggregation

Project Summary

In this project, Ahmed (Mo) and I seek to step around the usual “approaches to Alzheimer’s disease”, and develop a new approach to treatment based on artificial genes that sense the pathology and respond to any damage only as needed. We have termed these artificial genes, “Aggregation Sensitive Adaptive Therapeutic gene cassettes (ASATs)”. We will build up the technology incrementally over three aims. In the first aim, we will create a gene that SENSES the accumulation of Alzheimer pathology (focusing on aggregates of the protein tau, which accumulate in nerve cells as they start to get sick). As the nerve cells accumulate aggregated tau protein, the ASAT gene senses the pathology and turns on production of another gene, which in Aim 1 simply codes for a protein that is easily detectable. This simple system will help us to “tinker” with the sensing gene, to make it work as well as possible. In Aim 2, we will take the sensing gene from Aim 1, and add a THERAPEUTIC segment coding for an artificial protein designed to remove the Alzheimer pathology. We will compare multiple different possible THERAPEUTIC genes (i.e., segments) to identify the one that works best. In Aim 3, we will move from testing the ASAT in cultured cells to testing the ASAT in the brains of living animals. To accomplish this, we will take the finalized ASAT system and test its efficacy in a mouse model of Alzheimer’s disease that produces neurofibrillary tangles and shows neurodegeneration. This project is unique because it seeks to change the blunt approach of current genetics to a nuanced, adaptive approach that produces only as much genetic ASAT product as the cell needs to fix the disease. This approach has the added benefit that the ASAT should become less active as the pathology disappears, producing just enough to “get the job done”. We anticipate that this will produce a safer type of genetic therapy. Mo and I view this project as a harbinger for a broad range of future “tailored” therapeutic approaches. While we will apply this approach to Alzheimer’s disease first, the idea of having an adaptive therapeutic could be broadly applicable to a wide range diseases, extending from macular degeneration to cardiovascular disease and beyond.