Neurotrophic factors are small proteins that support the growth and survival of neurons. Neurotrophic factors function by binding specifically to the cell surface receptors that signal the neuron to survive. In addition to promoting neuron survival and suppressing new lesion formation, neurotrophic factors are capable of regenerating and regrowing damaged neurons.
The neurotrophic employed in this process - Brain-Derived Neurotrophic Factor (BDNF) – is known as a the most active neutrophin that stimulates and control neuron growth, especially for areas related to learning and memory. In addition to stimulating neurogenesis, BDNF also enhances synaptogenesis – the generation of synapses “bridges” between neurons and the nervous system. As such, BDNF serves as a converging point for several synaptic regulators – including β-amyloid monomers. β-amyloid monomers are neuroprotective and required for neuron survival, whereas neurotoxic β-amyloid oligomers “amyloid plaques” are causative of Alzheimer’s Disease. BDNF protects against β-amyloid-mediated toxicity by contributing to its degradation and preventing tau hyperphosphorylation. Reduced levels of BDNF are reported in patients diagnosed with Alzheimer’s Disease. The level of BDNF reduction correlates with the severity of disease progression including episodic memory performance - suggesting a strong link with disease pathology. Tau, a mediator of Aβ-induced toxicity, significantly downregulates BDNF expression – driving BDNF-related disease progression.
Macrophage-mediated drug delivery of BDNF for Alzheimer’s Disease is a novel approach to leverage the natural attraction of macrophages to inflammation caused by neuron degeneration to effectively deliver neurotrophic factors to the areas of the brain needed most. The strength of macrophage attraction is relative to the amount of inflammation, resulting in macrophage drug delivery only when needed. Engineering of CD34+ cells is accomplished using a macrophage-specific promoter, limiting drug production to macrophages as opposed to all CD34+ cell lineages.
There is extensive literature showing efficacy of BDNF in animal models for Alzheimer’s Disease. Proof of Concept pre-clinical studies with this technology are currently in progress.