Developing next generation AAV gene therapy vectors for specific and precise gene delivery

• Applicant: Dr. Robert Münch
• Subject Area: Virology ; Cell Biology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267238511

After a series of setbacks gene therapy is currently living up to its early promise. As recently shown, virus derived viral vectors have the potential to treat cancer or even help the blind to see by therapeutic gene delivery. The ultimate goal in human gene therapy is the specific and exclusive modification of the desired target cells upon systemic vector administration. Especially vectors derived from adeno-associated virus (AAV) are among the most promising gene transfer systems for in vivo application and have received broad attention due to substantial clinical benefit. However, these vectors still suffer from large shortfalls that do not yet meet modern gene therapy requirements regarding interaction with the immune system, specificity and detection of rare cell types. In this proposal we are aiming at the development of new AAV-based gene therapy vectors that can overcome these limitations by combing two state of the art molecular engineering approaches. We will optimize the AAV capsid to eliminate epitopes that are usually recognized by the human immune system and perform high throughput screens of chimeric AAV capsid libraries to establish new AAV capsids that provide efficient and specific gene transfer into desired cell types. Additionally we will develop a novel screening system for high affinity binding molecules which we will combine with selected vectors from the high throughput screen to generate AAV-based vectors with an as of yet unachieved level of specificity. To evaluate the feasibility of our approach we will establish AAV variants specific for hepatitis C infected cells and proof their therapeutic applicability in vitro and in vivo. Success of these studies will not only open the door for an array of new approaches to treat acquired human diseases in which the disease affected cells take on a new physical phenotype but also push the development of new AAV-based gene therapy vectors to the next level. Such vectors could be able to circumvent current limitations hampering the translation of preclinical AAV studies to the clinical environment.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Mark A. Kay