This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie COFUND grant agreement No 665735.

Bio4Med Research Projects:


<<< back to list

4: Bio4Med - Pharmacologically controlled BDNF gene therapy: a novel approach of optimized neurotrophin delivery for spinal cord injury

Supervisor:
prof. Malgorzata Skup
Foreign partner:
Dr Sebastian Kugler, CNS Gene Therapy Laboratory, University of Gottingen, Germany
WWW
http://en.nencki.gov.pl/laboratory-of-reinnervation-processes
Background:
Brain Derived Neurotrophic Factor (BDNF) is an excreted, small protein, that is necessary for neuronal survival and growth during development, and for maintenance of function of the majority of neurons in adulthood. BDNF acts through TrkB receptors on formation and strengthening of neuronal connections in the brain and spinal cord. After injury to the spinal cord, decreased levels of BDNF contribute to functional impairment and poor repair of neuronal circuits. Our recent work has demonstrated impressive recovery of locomotor functions after complete spinal cord transection (SCI) through viral vector mediated BDNF delivery, but the improvement was temporary. We presume that the reason for that attenuation was (1) a downregulation of TrkB receptor and (2) the network hyperexcitability developing over time. Our hypothesis is that the discontinuous BDNF expression will be therapeutically as efficient as continuous BDNF expression, but will prevent down-regulation of TrkB receptor sensitivity and hyperexcitability of motoneurons. State-of-the-art gene therapy vectors expressing BDNF under control of the "GeneSwitch" system, which is activated by the clinically approved small molecule drug mifepristone, will be produced. A series of vectors will be generated to optimize transcriptional control elements. We will also target BDNF expression to astrocytes or subtypes of neurons, in order to determine the optimal source for the neurotrophin. The student will learn SCI lesion, behavioral assessment of therapeutic efficiency and biochemical assays to understand the mechanisms of BDNF´s actions on excitatory and inhibitory neurons of the lesioned spinal cord.
Aim:
The aim of the project is to investigate if BDNF expressed from a regulated viral vector shows long-lasting therapeutic efficacy in a complete SCI model, sufficient to warrant initiation of clinical studies in patients with severe spinal cord injuries. We plan (1) to determine the optimal dosage and application routine of the clinically approved pharmacological compound used to control BDNF expression, (2) to carry on detailed behavioral, cellular and biochemical studies in rats to quantify therapeutic efficacy, evaluate BDNF spatio-temporal distribution in the spinal cord and correlate it with response of excitatory and inhibitory spinal circuits.
Requirements:
We are seeking highly motivated candidates with a strong academic record holding a MSc or equivalent in relevant subjects, with preference of Neuroscience, Medicine, Pharmacy • Significant background in molecular biology, neurobiology or pharmacology • Fluency and clarity in spoken English • Good written English • Effective written and verbal communication skills • Excellent IT skills. Word, Excel and Power Point • Well-organized, attention to detail and ability to meet deadlines Candidates must not have resided or carried out their main activity (work, studies, etc.) in Poland for more than 12 months in the past 3 years. • Ability to think logically, create solutions and make informed decisions. • Ability to analyse and write up data • Experience of working collaboratively in a research environment. • Commitment to high quality research. • Commitment to the Nencki Institute policy of equal opportunity and the ability to work harmoniously with colleagues and students of all cultures and backgrounds. Desirable: Experience with one or more of the domains in the field of Neuroscience in particular handling of laboratory animals (rats), histology of brain sections and/or neuroimaging and analysis is a plus point.