About this Research Topic
Neurotrophins (NTs) are a family of proteins that induce the survival, development, and function of neurons. NTs help to stimulate neurogenesis and stimulate differentiation of progenitor cells to form neurons and regulate neuronal plasticity and sprouting. They include the prototypic Nerve Growth Factor (NGF), as well as BDNF, NT3, NT4-5, NT6, and NT7 and exert pleiotropic actions not only on CNS and PNS, but also beyond the nervous system.
Early and progressive dysregulation of NGF and BDNF pathways are particularly involved in the aging process and contribute to cognitive decline as observed in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). The cholinergic system of the human brain has been attributed to be the master regulator of executive and mnemonic functions. It depends throughout life from NGF supply from target neurons in the cortex and hippocampus, which loss is associated with cognitive decline in Mild Cognitive Impairment and AD.
Despite huge efforts in identifying disease-modifying drugs, approved anti-AD molecules consist of symptomatic compounds (the cholinesterase inhibitors donepezil, rivastigmine, and galantamine; and the glutamate receptor antagonist memantine), providing only minor and temporary attenuation of cognitive deficits, without any impact on disease progression or severity. Treatment of other neurodegenerative diseases like PD, Huntington’s disease (HD), frontotemporal dementia, Lewy body dementia have made modest progress from a therapeutic point of view.
Over the last decade, exogenous NTs have been shown to alleviate and/or delay neuronal pathology in several models of neurodegeneration. Accordingly, their clinical use has been attempted or suggested for a broad range of age-related, genetic or neuroinflammatory conditions, like AD, PD, HD, autism, schizophrenia, glaucoma, multiple sclerosis, Down’s syndrome, traumatic brain injury, and type 2 diabetes, but also as support to stem-cell therapy.
However, despite several encouraging preclinical studies on animal models and advanced clinical trials in humans, the therapeutic potential of NTs, and of NGF in particular, as treatment for neurodegeneration demands further implementation. Overall, long-term, and effective therapy for alleviating cognitive impairment is a major unmet need.
The main limitations of NGF and other NTs treatments in treating CNS diseases are represented by their inability to cross the blood-brain barrier, their poor oral bioavailability, as well as mechanism-based side-effects. To circumvent these restraints, gene therapy, cellular-based implants, novel selective NGF mimetics, as well as ocular or nasal administration, and other new brain delivery systems have been developed and have produced promising results in animal models of neurodegenerative diseases and in initial clinical testing.
The scope of this special issue is to review the rationale and the results of the most innovative neurotrophic biodelivery approaches that have been recently developed. We will also focus on the most relevant results obtained in the non-clinical setting, as well as examine the most promising clinical candidates that have the potential to modify the natural history of different neurodegenerative diseases, including AD and PD.
Early and progressive dysregulation of NGF and BDNF pathways are particularly involved in the aging process and contribute to cognitive decline as observed in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). The cholinergic system of the human brain has been attributed to be the master regulator of executive and mnemonic functions. It depends throughout life from NGF supply from target neurons in the cortex and hippocampus, which loss is associated with cognitive decline in Mild Cognitive Impairment and AD.
Despite huge efforts in identifying disease-modifying drugs, approved anti-AD molecules consist of symptomatic compounds (the cholinesterase inhibitors donepezil, rivastigmine, and galantamine; and the glutamate receptor antagonist memantine), providing only minor and temporary attenuation of cognitive deficits, without any impact on disease progression or severity. Treatment of other neurodegenerative diseases like PD, Huntington’s disease (HD), frontotemporal dementia, Lewy body dementia have made modest progress from a therapeutic point of view.
Over the last decade, exogenous NTs have been shown to alleviate and/or delay neuronal pathology in several models of neurodegeneration. Accordingly, their clinical use has been attempted or suggested for a broad range of age-related, genetic or neuroinflammatory conditions, like AD, PD, HD, autism, schizophrenia, glaucoma, multiple sclerosis, Down’s syndrome, traumatic brain injury, and type 2 diabetes, but also as support to stem-cell therapy.
However, despite several encouraging preclinical studies on animal models and advanced clinical trials in humans, the therapeutic potential of NTs, and of NGF in particular, as treatment for neurodegeneration demands further implementation. Overall, long-term, and effective therapy for alleviating cognitive impairment is a major unmet need.
The main limitations of NGF and other NTs treatments in treating CNS diseases are represented by their inability to cross the blood-brain barrier, their poor oral bioavailability, as well as mechanism-based side-effects. To circumvent these restraints, gene therapy, cellular-based implants, novel selective NGF mimetics, as well as ocular or nasal administration, and other new brain delivery systems have been developed and have produced promising results in animal models of neurodegenerative diseases and in initial clinical testing.
The scope of this special issue is to review the rationale and the results of the most innovative neurotrophic biodelivery approaches that have been recently developed. We will also focus on the most relevant results obtained in the non-clinical setting, as well as examine the most promising clinical candidates that have the potential to modify the natural history of different neurodegenerative diseases, including AD and PD.
Keywords: NGF, neurotrophins, CNS delivery, neurodegeneration, AD, PD
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