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Method for the selection of modulators of bdnf

BDNFDrug Screening assayNeurodegenerative disordersNeuroprotectionPsychiatric disorders

Introduction

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is the most prevalent growth factor in the central nervous system. BDNF is a potent neuroprotective agent promoting survival and differentiation during neuronal development, and modulating synaptic strength, learning and memory, and spinal mechanisms for pain in adulthood. The present invention concerns a method for the identification of specific compounds able to modulate BDNF, for the development of drugs for the treatment of neurodegenerative and neuropsychiatric diseases or addiction.

Technical features

We developed a High Throughput cell-based assay using human cell lines to identify natural or synthetic compounds that enhance or decrease translation of the 4 most abundant BDNF transcript variants. Unlike pre-existing assays that measure the effects on the mRNA coding for BDNF, this assay has the exclusive advantage of being able to measure the effect of any compound’s translation into protein starting from the four main transcripts encoding the BDNF. Given the strong differences in the translatability of individual BDNF transcripts, with variations in protein production up to 30 folds, our assay is distinct from all previous approaches as it allows to discriminate the effects of test drugs at the level of translation. The assay is based on stable-transfected human neuronal cell lines and uses Luciferase as reporter gene. It can be used on a flexible 96-1536 well plate format, and can be transferred to a different cell line. At present, the assay has been optimized in one human neuroblastoma cell line.

Possible Applications

  • Identify drugs to reduce excess of BDNF synthesis in: Epilepsy and Addiction.
  • Identify drugs to increase BDNF synthesis in: psychiatric diseases and in other diseases with cognitive deficits; Alzheimer’s disease and other dementias; neurodevelopmental orphan diseases including autism, schizophrenia, Rett Syndrome, Prader-Willi syndrome, Fragile-X syndrome; Neurodegenerative diseases such as Huntington’s syndrome, and Multiple Sclerosis.

Advantages

  • Patented, unique assay;
  • Cell-based assay for transcript-specific BDNF translation;
  • Time saving, because allows testing the major BDNF variants in four ready-to-plate stable cell lines;
  • Amenable to high throughput, small volume set-up using 96/384/1536-well plates;
  • Robustly quantitative, because based on luciferase which displays a high dynamic range of responsiveness;
  • Able to identify drugs that increase or reduce BDNF translation, which is a unique and groundbreaking approach.