Engineered BDNF producing cells as a potential treatment for neurologic disease

ABSTRACT

Introduction: Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression.

Areas covered: The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF.

Expert opinion: Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic.

KEYWORDS:

• BDNF
• Mesenchymal Stem Cell
• Gene Therapy
• Huntington’s disease
• Neurodegeneration

Article highlights

• Brain-derived neurotrophic factor is a critical neurotrophin regulating cell survival, neuronal outgrowth, and plasticity.

• Brain-derived neurotrophic factor regulates neurogenesis, synaptic plasticity, and apoptosis via PI3K-AKT, MAPK, ERK, and y-CaM kinase pathway.

• Dysregulation of brain-derived neurotrophic factor has been implicated in many disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease.

• Delivery of brain-derived neurotrophic factor has been the major hurdle to its use in a clinical setting.

• Engineered mesenchymal stem cells may circumvent many of the issues surrounding brain-derived neurotrophic factor delivery.

This box summarizes key points contained in the article.

Acknowledgments

Support for this project was provided by a NIH NIGMS Predoctoral Fellowship T32GM099608 (Deng), NSF GRFP 2011116000, NIH T32-GM008799, NSF GROW 201111600, T32-HL086350 NIH (Anderson), NRSA Postdoctoral Fellowship F32NS090722 (Fink), a NIH Director’s transformative award 1R01GM099688 (Nolta), The Stewart’s and Dake Family Gift (Nolta/Fink), California Institute for Regenerative Medicine (CIRM) DR2-05415 (Wheelock/Nolta), and philanthropic donors from the HD community, including the Roberson family and Team KJ.

Declaration of interests

This paper was supported by funds from the NIH, California Institute for Regenerative Medicine, and unrestricted philanthropic gifts. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.