We have identified the presence of the poorly characterized precursor proNGF-A in human tissues, deposited its coding nucleotide sequence (GenBank MH358394) and demonstrated its neuroprotective and neurotrophic activity in vitro and in vivo. We inserted mutations into the native molecule, identified through computational analysis, which allow proNGF-A production by eukaryotic expression systems, through a method currently validated on a laboratory scale. The human proNGF-A peptide (hproNGF-A) which forms the subject of the invention, is characterized by a molecular weight of 34 kDa, a high resistance to degradation by the extracellular proteases plasmin and MMP, by a length of 296 amino acids and a theoretical isoelectric point of about 9.5.
The use of the peptide nerve growth factor (NGF) is indicated for the treatment of neurodegenerative diseases and for the outcomes of severe neurotrauma. However, this neutrophin suffers from some important limitations, related to the activation of the TrkA receptor, which generates a hyperalgesic effect and a potential pro-tumor activity. Furthermore, NGF is extremely vulnerable to the action of extracellular matrix proteases (MMPs). Unlike the NGF peptide, proNGF-A exerts its neuroprotective action by binding to the p75NTR receptor. This potentially limits the occurrence of side effects. Furthermore, proNGF-A is extremely more resistant than NGF, allowing a more favorable modulation of therapeutic dosages in terms of safety. The production of the peptide through eukaryotic systems also guarantees greater biocompatibility.
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