Gene Knock Up at the post-transcriptional level to model and treat neurological disease

One of the important unresolved questions in biomedicine is our inability to conditionally modulate endogenous gene expression limited to naturally expressing cells.

This inability hinders association of gene expression levels to human disease and development of novel treatments, especially in tissues where expression site and levels are critically important such as the brain.

I have made substantial progress towards solving this problem by showing that it is possible to conditionally increase endogenous gene, such as neurotrophic factor GDNF expression by conditionally replacing its 3´UTR.

Demonstrating the power to discover I used patient analysis and this approach to identify increased GDNF as a potential driver of schizophrenia in a sub-group of patients and identified adenosine receptor Adora2a and GDNF receptor RET as potential new precision medicine to treat GDNFhigh sub-group of schizophrenia.

Here I propose further studies to proceed towards clinical trials.

Next, using new CRISPR-Cas9 tiling library screen I found that it is possible to identify single gRNAs which either enhance or reduce expression from endogenous mRNA via 3´UTR editing, establishing new research and treatment tool.

Now we can test my hypothesis that increasing endogenous autophagy, protein folding and neurotrophic function may reverse the progression of currently untreatable Parkinson´s disease better than current ectopic gene expression tools.