Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application? (original) (raw)
Related papers
Nerve growth factor: from the early discoveries to the potential clinical use
Journal of Translational Medicine, 2012
The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.
Nerve growth factor: basic studies and possible therapeutic applications
Growth Factors, 2013
The nerve growth factor (NGF) belongs to a family of neurotrophic factors called neurotrophins. It was discovered as a molecule that stimulates the survival and maturation of developing neurons in the peripheral nervous system and has later been shown to protect adult neurons in the degenerating mammalian brain. Basic and clinical studies have been undertaken to use NGF as a therapeutic agent aimed at restoring and maintaining neuronal function in the central nervous system and to determine the mechanisms to safely deliver the molecule into the brain. Recent studies have also recognized that the role of NGF extends far beyond the horizon of nerve cells and even beyond the peripheral and central nervous system. Studies published from our laboratory have shown that topical application of NGF possesses a protective action on human pressure ulcer, corneal ulcer and glaucoma. Here, we will review these studies, supporting the therapeutic potential of NGF.
Efficient Delivery of Nerve Growth Factors to the Central Nervous System for Neural Regeneration
Advanced Materials, 2019
Nerve growth factor (NGF), the first discovered member of the neurotrophin family, plays a major role in the neural development of the central nervous system (CNS). [1-3] In adults, endogenous secretion of NGF is involved in a plethora of The central nervous system (CNS) plays a central role in the control of sensory and motor functions, and the disruption of its barriers can result in severe and debilitating neurological disorders. Neurotrophins are promising therapeutic agents for neural regeneration in the damaged CNS. However, their penetration across the blood-brain barrier remains a formidable challenge, representing a bottleneck for brain and spinal cord therapy. Herein, a nanocapsule-based delivery system is reported that enables intravenously injected nerve growth factor (NGF) to enter the CNS in healthy mice and nonhuman primates. Under pathological conditions, the delivery of NGF enables neural regeneration, tissue remodeling, and functional recovery in mice with spinal cord injury. This technology can be utilized to deliver other neurotrophins and growth factors to the CNS, opening a new avenue for tissue engineering and the treatment of CNS disorders and neurodegenerative diseases.
Nerve Growth Factor: A Focus on Neuroscience and Therapy
Nerve growth factor (NGF) is the firstly discovered and best characterized neurotrophic factor, known to play a critical protective role in the development and survival of sympathetic, sensory and forebrain cholinergic neurons. NGF promotes neuritis outgrowth both in vivo and in vitro and nerve cell recovery after ischemic, surgical or chemical injuries. Recently, the therapeutic property of NGF has been demonstrated on human cutaneous and corneal ulcers, pressure ulcer, glaucoma, maculopathy and retinitis pigmentosa. NGF eye drops administration is well tolerated, with no detectable clinical evidence of systemic or local adverse effects. The aim of this review is to summarize these biological properties and the potential clinical development of NGF.
Nerve growth factor in Alzheimer’s disease : biological effects and therapeutic potential
2017
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder against which there is yet no disease modifying or curative treatment. Degeneration of cholinergic basal forebrain (CBF) neurons plays a role in the pathogenesis of AD and these neurons are highly dependent on nerve growth factor (NGF) for growth and survival. NGF has been proposed as a potential therapy for AD, but NGF does not pass the blood-brain barrier and must be delivered locally to the CBF to avoid side-effects. We tested targeted delivery of NGF to the CBF, using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-man trial in AD patients. The primary objective was to examine safety and tolerability and the secondary objective to test for possible effects on cognition and biomarkers. Ten AD patients were implanted stereotactically with NGF-ECB implants targeting the CBF during 12 months (papers II-IV) or 6 months (paper V). Six patients were implanted with firstgeneration implants, which at implan...
Journal of Biochemical and Biophysical Methods, 2001
Nerve growth factor (NGF) has been suggested to be of therapeutic benefit to patients with Alzheimer's disease. One of the early changes in this disease is a loss of cholinergic function within the brain, and NGF is able to rescue cholinergic neurons both in vitro and in vivo. We describe the production of recombinant human b-NGF (rhNGF), using baculovirus infection of insect cells; its purification, formulation and subsequent stability for use in clinical trials. Tests were also carried out to monitor release of protein from infusion pumps and catheters for intracerebroventricular administration (icv). Initial problems with non-specific binding were overcome using a blocking formula.
International journal of molecular sciences, 2017
Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and paracrine interactions which will be described herein. It was of similar significance in establishing the identity and unique roles of neurotrophic factors in the development and maintenance of the peripheral and central nervous systems. Finally, it contributed to many advances in the elaboration of cell surface receptor mechanisms and intracellular cell signaling. As such, it can be considered to be a "molecular Rosetta Stone". In this brief review, the highlights of these various studies are summarized, particularly as illustrated by their coverage in the 13 NGF international meetings that have been held since 1986.
Molecular Therapy, 2010
Nerve growth factor (NGF) prevents cholinergic degeneration in Alzheimer's disease (AD) and improves memory in AD animal models. In humans, the safe delivery of therapeutic doses of NGF is challenging. For clinical use, we have therefore developed an encapsulated cell (EC) biodelivery device, capable of local delivery of NGF. The clinical device, named NsG0202, houses an NGF-secreting cell line (NGC-0295), which is derived from a human retinal pigment epithelial (RPE) cell line, stably genetically modified to secrete NGF. Bioactivity and correct processing of NGF was confirmed in vitro. NsG0202 devices were implanted in the basal forebrain of Göttingen minipigs and the function and retrievability were evaluated after 7 weeks, 6 and 12 months. All devices were implanted and retrieved without associated complications. They were physically intact and contained a high number of viable and NGF-producing NGC-0295 cells after explantation. Increased NGF levels were detected in tissue surrounding the devices. The implants were well tolerated as determined by histopathological brain tissue analysis, blood analysis, and general health status of the pigs. The NsG0202 device represents a promising approach for treating the cognitive decline in AD patients.
Nerve growth factor as potential target in central nervous system disorders: A review
Nerve growth factor (NGF) is a member of neurotrophin family playing important role in growth, development and survival of neurons. This protein is synthesized and released by target tissues and it protects the neurons innervating that tissue from undergoing programmed cell death (apoptosis). NGF exerts its biological action by acting on specific receptor tropomyosin kinase receptor A (TrkA) activating the cytosolic/endosomal pathways which include Ras-mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K) -Akt, and Phospholipase C (PLC) –γ. NGF interaction with p75 pan-neurotrophin receptor (p75NTR) plays an important role in apoptosis. The function of NGF in neuronal survival and death makes it a potential target in nervous system disorders. NGF is found to play a major role in diseases like Alzheimer’s disease, Parkinson’s disease, amyloid lateral sclerosis, multiple sclerosis and peripheral neuropathies and can have major role in other diseases too. NGF modulator studies are still going on and some drugs are in clinical trials which may produce beneficial outcomes. The current review focuses on the various aspects of NGF as therapeutic tool. Keywords: Nerve growth Factor, TrkA, p75NTR, Alzheimer’s disease, Parkinson’s disease, amyloid lateral sclerosis, multiple sclerosis, peripheral neuropathies.
Behavioural Brain Research, 1993
We report on the clinical outcome of a first case of intracranial infusion of nerve growth factor (NGF) to an Alztmimer patient. The therapeutic attempt is based on animal research showing that NGF stimulates central cholinergic neurons of the type known to be lost during the development of Alzheimer's disease (AD). Furthermore, our own previous clinical experience of infusing NGF to support the survival of intracranially transplanted adrenal chromaffin cells to Parkinsonian patients indicate this approach to be technically possible and safe and clinically of significant potential. Our first case was a 69-year-old woman, with symptoms of dementia since 8 years, lntraventricular infusion of 6,6 mg NGF over three months resulted in a marked transient increase in uptake and binding of [LIC]nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF infusion, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects of the NG F infusion were found. The results of this single case indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.