The History of Nerve Growth Factor: From Molecule to Drug

Abstract

Nerve growth factor (NGF), the first neurotrophin to be discovered, has a long and eventful research journey with a series of turning points, setbacks, and achievements. Since the groundbreaking investigations led by Nobel Prize winner Rita Levi-Montalcini, advancements in the comprehension of NGF's functions have revolutionized the field of neuroscience, offering new insights and opportunities for therapeutic innovation. However, the clinical application of NGF has historically been hindered by challenges in determining appropriate dosing, administration strategies, and complications related to the production process. Recent advances in the production and scientific knowledge of recombinant NGF have enabled its clinical development, and in 2018, the United States Food and Drug Administration approved cenegermin-bkbj, a recombinant human NGF, for the treatment of all stages of neurotrophic keratitis. This review traces the evolutionary path that transformed NGF from a biological molecule into a novel therapy with potential research applications beyond the eye. Special emphasis is put on the studies that advanced NGF from discovery to the first medicinal product approved to treat a human disease.

Keywords: biomolecule; cenegermin; drug discovery; nerve growth factor; neurotrophic keratitis; neurotrophins.

Figure 1

NGF-related upstream and downstream pathways and clinical application overview [10,19]. NGF (shown as a crystal structure comprising 2 monomers interconnected noncovalently through a cysteine knot structure) binds and activates TrkA and p75NTR, resulting in downstream survival pathway activation via NFκB and AKT, inhibition of neurite growth via AKT, and promotion of neurite growth via MAPK. AKT, protein kinase B, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa B; NGF, nerve growth factor; p75NTR, p75 neurotrophin receptor; PI3K, phosphoinositide 3-kinase; PLCγ, phospholipase C gamma; SHC, SHC-transforming protein 1; TrkA, tropomyosin receptor kinase A.

Figure 2

Recombinant human NGF production and cenegermin-bkbj workflow. (A) rhNGF production begins with a gene that codes for the human proNGF protein cloned into an expression vector to create a plasmid, resulting in a strain of the Escherichia coli microorganism with the necessary information to express the protein. A series of fermentations in E. coli are conducted, enabling recombinant protein production. The protein accumulates in the cytoplasm of the microorganism as inclusion bodies, which are recovered through purification. (B) Workflow of cenegermin-bkbj production. ERP, enterprise resource planning; IB, inclusion body; NGF, nerve growth factor; rhNGF, recombinant human NGF.