Therapeutic neuroprotection by an engineered neurotrophin designed to broadly activate Trk-receptors and to circumvent p75 receptors.

The neurotrophins are a family of growth factors that bind and activate two types of cell surface receptors: the Trk family, and p75. TrkA, TrkB or TrkC are bound preferentially by NGF, BDNF, or NT3 to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins. Paradoxically, in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. Hence, the receptors can mediate opposite activities in a ligand-dependent manner. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D), to reduce p75 binding (mutant RK), or combining these features in a molecule that activates TrkA, TrkB and TrkC with reduced p75 binding (mutant DRK). In mouse neurodegenerative disease models in vivo, the DRK protein protects a broader range of stressed neurons and is a superior therapeutic agent compared to D, to RK, or to wild-type neurotrophins. This work rationalizes neuroprotective therapeutic strategies based on the biology of each receptor subtype in disease states. Significance Statement Neurotrophins are growth factors NGF BDNF and NT3, each can activate a TrkA or TrkB or TrkC receptor respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.