Tomas Björklund | PhD, Associate Professor
Earlier research work
I have over ten-year of experience in the fields of gene therapy, in vivo studies and Parkinson’s disease (PD). My earlier research work has focused on the development of novel AAV (adeno-associated viral) vector based therapies and disease models for PD and related disorders. Two major lines have emerged from that; an optimized therapy for PD using AAV mediated enzyme replacement and novel disease models for PD, Huntington’s disease and dementia with Lewy bodies.
AAV-mediated enzyme replacement has become a very promising clinical candidate that is now being taken by my own company, Genepod Therapeutics, towards clinical trials in Parkinson patients. The disease models we have established using AAV-vectors have started to gain significant momentum and the results have been replicated in a number of labs.
We have recently completed two major studies utilizing a second generation, inhibitory chemogenetic receptor (commonly named DREADDs) in advanced in vivo experiments on cell transplantation for PD where we have for the first time been able to show important mechanisms underlying graft-induced abnormal involuntary movements or dyskinesias (published in Neuron).
Current research work
Translational combination of genome editing and chemogenetic modulation to dissect the striatal circuitry in vivo
The main goal of this project is to validate our newly identified mechanism underlying the emergence of dyskinesias in PD and find a clinically applicable therapeutic approach to modulate this target. In our completed study (Neuron 2016), we have identified the 5-HT6 receptor as a potential therapeutic target in GIDs. In a follow-up study, we have furthered this approach and found mechanistic similarities between the GID and L-DOPA induced dyskinesias (LIDs). Recent studies point to the striatal cholinergic interneurons (AChINs) being a key player in the emergence and maintenance of LIDs in PD and that they can be inhibited through administration of muscarinic receptor antagonists. Using a novel ChAT-Cre transgenic rat in combination with the novel set of AAV-mediated orthogonal DREADDs, we have also shown that AChINs modulate LIDs in PD. In our ongoing work, we seek to bring all these data together and experimentally define a unified model of the Serotonin/Dopamine/Acetylcholine interaction in PD.
Barcode-based genetic screening of novel AAV serotypes for translational gene therapy
We have successfully developed a novel methodology to uniquely label each viral particle in a preparation with a unique identifier sequence (20 nucleotide random sequence) that is inserted in the 3’UTR (untranslated region) of mRNA expressed from the cell infected by that specific particle. Details on this process can be found in our Scientific reports 2016 paper. Using this approach, we have been able to develop an entirely new way to produce, screen and select new AAV serotypes that harbour infectivity profiles that are tailor-made for specific clinical applications.