You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1 Yousra El Ouaamari -- 3329 2023-03-09 11:05:39 |
2 format Jason Zhu Meta information modification 3329 2023-03-10 03:08:49 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
El Ouaamari, Y.; Van Den Bos, J.; Willekens, B.; Cools, N.; Wens, I. Delivery of Neurotrophic Factors’ and Associated Challenges. Encyclopedia. Available online: https://encyclopedia.pub/entry/42014 (accessed on 13 December 2025).
El Ouaamari Y, Van Den Bos J, Willekens B, Cools N, Wens I. Delivery of Neurotrophic Factors’ and Associated Challenges. Encyclopedia. Available at: https://encyclopedia.pub/entry/42014. Accessed December 13, 2025.
El Ouaamari, Yousra, Jasper Van Den Bos, Barbara Willekens, Nathalie Cools, Inez Wens. "Delivery of Neurotrophic Factors’ and Associated Challenges" Encyclopedia, https://encyclopedia.pub/entry/42014 (accessed December 13, 2025).
El Ouaamari, Y., Van Den Bos, J., Willekens, B., Cools, N., & Wens, I. (2023, March 09). Delivery of Neurotrophic Factors’ and Associated Challenges. In Encyclopedia. https://encyclopedia.pub/entry/42014
El Ouaamari, Yousra, et al. "Delivery of Neurotrophic Factors’ and Associated Challenges." Encyclopedia. Web. 09 March, 2023.
Delivery of Neurotrophic Factors’ and Associated Challenges
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24043866

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases.

neurotrophic factors regenerative therapy neurodegenerative diseases

1. Introduction

Neurodegenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS), Alzheimer′s disease (AD), Parkinson′s disease (PD), Huntington′s disease (HD), amyotrophic lateral sclerosis (ALS), and in acute cases, spinal cord injury (SCI), are still incurable and have high individual and societal costs [1][2][3]. PD and AD are the most common neurodegenerative diseases. As the world′s population ages, the prevalence of AD and PD is rapidly increasing. It is estimated that 50 million people worldwide suffer from neurodegenerative diseases, and this number will rise to 115 million by 2050 [4].
Unfortunately, currently available treatment options are inadequate to halt neurodegenerative processes [5][6]. Moreover, the understanding of the pathogenic processes and the consequent development of effective treatments is significantly complicated by the complexity of the mechanisms associated with neuronal loss and the conflicting physiological causes of these diseases. Furthermore, the difficulty in addressing widespread neuronal cell death, combined with the enormous limitations for the vast majority of drugs not to cross the blood–brain barrier (BBB), further complicates the treatment of these diseases [7][8].
From an evolutionary point of view, the nervous system would be able to protect itself from any injury [9]. In the early 20th century, pioneering work by Tello and Cajal demonstrated that the CNS has the ability to regenerate itself after injury [10][11][12]. In recent years, researchers have accumulated detailed in vitro and in vivo mechanistic evidence supporting the idea that an innate self-maintenance program is activated in the brain, not only during inflammatory and degenerative diseases, but also in healthy individuals [11][13][14]. These observations support the idea that chronic inflammatory and degenerative disorders of the brain can be the result of defective repair mechanisms, rather than uncontrollable pathogenic events [11][15][16][17].
Neurotrophic factors (NTFs) and their receptors play a crucial role in neural cell maturation and proliferation. NTFs regulate the development and survival of neurons, and they appear to be involved in the endogenous neuroprotection of different neurons. Several studies have reported that NTFs, particularly glial cell-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), act regeneratively in different animal models [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] and patients [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] with neuroinflammatory and neurodegenerative diseases. Consistent with their known role in maintaining neuronal homeostasis, these NTFs, with regenerative properties, have been proposed as novel therapies for several neuroinflammatory and neurodegenerative diseases [73][74][75].

2. Administration of NTF by Direct Infusion in the CNS

Various techniques have been used to get NTFs into the brain. The best known technique is direct intracerebroventricular (ICV) infusion. In particular, recombinant human (rh) GDNF and 125Iodine-labelled GDNF (125I-GDNF) have been shown to diffuse into the deep brain structures of rats [76][77], not only to significantly increase striatal and nigral dopamine (DA) levels, but also to increase hypothalamic DA levels, which could explain the decreased food and water consumption and body weight observed in in vivo experiments [78][79]. ICV injection of GDNF into 6-hydroxydopamine (6-OHDA)-treated rats, an animal model of PD, also appears to result in improved locomotor performance [78][79]. Furthermore, the ICV delivery route seems suitable for therapies that need to reach the BFCNs. Early and progressive degeneration of BFCNs contributes substantially to cognitive impairments of AD. Since BFCNs extend their axons through the hippocampus and neocortex, NGF administered in the lateral ventricle can act on the TrkA receptor to transmit trophic support signals to BFCNs. This approach has been shown to be particularly effective in preventing loss of BFCNs in rodents associated with injury and ageing [80][81][82]. However, the small volume of the rodent brain compared to the human brain raises important questions about the applicability of this technique in clinical studies. Therefore, ICV injections were also performed in non-human primates [83][84][85]. GDNF has been shown to produce significant improvements in motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys, a model of PD [83][86], and improvements in motor impairment and reductions in l-dopa-induced dyskinesia in marmosets [84]. In an autoradiographic study of the distribution of 125I-GDNF administered in the lateral ventricles of rhesus monkeys with a MPTP lesion, GDNF was not found to diffuse readily into the putamen. This finding contrasts with similar studies in rodents [76][77], suggesting that the success of ICV infusion in rodents might be a product of the smaller diffusion distance within their brain [78][79]. Moreover, the ICV delivery route was associated with serious side effects [80], such as hyperinnervation of cerebral blood vessels [82], hypophagia [80][81], Schwann cell hyperplasia with sprouting of sensory and sympathetic neurons [87], neuropathic pain [80], and dyskinesia [83][84][86], providing profound contra-indications for the applicability in clinical trials.
Because of these ICV-related side effects, the study by Tuszynski et al. [88] investigated whether intra-parenchymal infusion would be a well-tolerated way to administer NTFs to degenerating cholinergic neurons. In particular, intraparenchymal NGF infusion prevented degeneration of BFCNs, whereas glial responses were minimal in adult rats that underwent complete unilateral fornix transections, followed by intraparenchymal infusions of recombinant human NGF for a 2-week period. In addition, no apparent toxic effects of the infusions were observed, according to the researchers [88]. Other studies aimed to administer NTFs by a less invasive method. The group of Braschi et al. [20] tested whether intranasal (IN) administration of different concentrations of BDNF in AD11 transgenic mice, a model of AD, was able to rescue neuropathological and memory deficits. They found that IN administration of BDNF, but not with PBS, was adequate to completely rescue the performance of AD11 mice in both the object recognition test and the object context test. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an improvement in AD-like pathology, amyloid-β (Aβ) load, tau hyperphosphorylation, and cholinergic deficiency [20]. Similarly, IN administration of NGF to Aβ peptide-expressing traumatic brain injury (TBI) rats, which are at risk of AD in later life, caused a marked reduction in Aβ42 deposits and restored motor and behavioural function [19]. Features such as non-invasive manipulations, rapid absorption rate, easy repetitive dosing, and reduction of non-target biodistribution make IN administration superior to the systemic and ICV routes of administration [18][19].
Finally, studies examined the effects of continuous intraputamenal administration of GDNF in both aged and MPTP-lesioned non-human primates [89][90][91]. Histological and biochemical analysis showed an increase in cell size and the number of dopaminergic neurons within the substantia nigra, as well as increased fibre density in the caudate nucleus, putamen, and globus pallidus. Primates with MPTP lesions showed improvements in the primate PD rating scale, whilst aged monkeys demonstrated improvement in general motor performance at high doses and increases in hand speed [89][90][91]. To assess the possible side effects of continuous administration of GDNF, a six-month toxicity study was conducted in rhesus monkeys. The results cast considerable doubt about the neuro-restorative potential of GDNF for the treatment of PD, given that they identified a number of pathological markers of toxicity, including reduced food intake and weight loss, meningeal thickening, and most concerning, multifocal cerebellar Purkinje cell loss [30]. Apart from the above-mentioned side effects, direct administration of NTFs into the brain also had some practical problems, such as invasiveness, BBB permeability [7][8][92], poor half-life, and rapid degradation [93]. This led to studies using cell therapy, where cells were modified to produce a specific protein.

3. Cells Modified to Express Neurotrophic Factors

During the last years, different cell types have been utilized to deliver NTFs to the injured sites. Mesenchymal stromal cells (MSCs) are described as adherent, fibroblast-like cells with prominent proliferation capacity [41][49][50][94]. Because of their low immunogenicity (low expression levels of major histocompatibility complex (MHC) class II), MSCs can survive after administration [95]. The existence of such capabilities makes MSCs a safe, tolerable, and efficient biological vector for the generation and delivery of therapeutic agents, such as NTFs, to the target sites [41][49][50]. Furthermore, different routes of administration were used to administer the modified MSCs, resulting in different outcomes. In a study by Suzuki et al. [50], human MSCs (hMSCs), derived from neonatal bone marrow aspirates which were modified to express GDNF, were administered intramuscularly as a "Trojan horse" to superoxide dismutase (SOD1)G93A rats, a rat model of familial ALS, to deliver GDNF to the terminals of motor neurons and to skeletal muscle. hMSC-GDNF survived in the muscle, secreted GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord in the mid-stage of the disease. Moreover, hMSC-GDNF significantly slowed down disease progression [50]. In addition, several improvements have been reported when CNTF- [51], NT-3- [52], and BDNF-modified [53] MSCs were administered directly into the spinal cord of SCI rats, such as improvement in behavioural scores, motor function, axonal regeneration, and neuronal survival [51][52], and restoration of diaphragm muscle function [53]. Positive results with MSCs expressing NTFs were also observed after intravenous (iv) administration. A remarkable recovery of neuronal function was observed and demyelination was significantly reduced in EAE mice: the cumulative clinical scores were significantly decreased, and the disease onset was statistically delayed, after iv MSC-CNTF [54] and MSC-BDNF administration [96]. Moreover, BDNF-expressing MSCs can also reduce striatum atrophy and increase neurogenesis in HD mouse models [21]. In summary, MSCs represent a promising tool for cell therapy. There is currently much interest in the use of MSCs for the treatment of neurodegenerative diseases. There are several studies using the innate trophic support of MSCs or increased support by NTFs, such as the administration of BDNF, CNTF NTF-3, or GDNF to the CNS to support damaged neurons, using genetically engineered MSCs as delivery tools. Biosafety could be a potential difficulty in cell therapies when using genetically engineered MSCs. The random integration of vectors with genes for neurotrophic or other factors may pose the risk of insertional integration. However, homologous recombination and targeted gene transfer are advancing rapidly.
Neural stem cells (NSCs) are also used as a NTF vector, resulting in several positive effects. NSCs are characterised as multipotent and self-renewing cells with the capacity to differentiate into mature neurons and neuroglia cells [22][23][24][25]. In a rodent model of cervical SCI, it was shown that GDNF-expressing human induced pluripotent stem cell-derived NSCs (hiPSC-NSCs) showed greater differentiation into a neuronal phenotype than unmodified hiPSC-NSCs [26]. Furthermore, several improvements were seen with NSCs expressing GDNF in SOD1G93A ALS rats, when administered in the motor cortex [23] and in the spinal cord [24]. The results show improved survival, as well as enhanced proliferative and neuroprotective properties [23][24]. Moreover, human GDNF-expressing NSCs duly migrated to the disease site and integrated into the CNS after administration into the spinal cord of SOD1G93A ALS rats [24]. In addition, it has been shown that GDNF-expressing NSCs administration in the lateral ventricle promotes axonal regeneration and remyelination in chronic EAE rats [25].
A number of studies have indicated that immune cells are also useful as therapeutic biosystems to deliver various molecules into target areas [27][28]. Among the subsets of immune cells, macrophages are the most suitable target cells, as they are activated soon after the onset of the inflammatory response, can cross the BBB, and move to sites of neuronal degeneration [27][28]. In this regard, the monocyte-macrophage lineage could represent an efficient cellular system to deliver NTFs at the site of injury within the CNS. To support this hypothesis, Biju et al. used ex vivo transduced bone marrow-derived macrophages to deliver GDNF [27]. Axonal regeneration and retention of tyrosine hydroxylase (TH+) neurons were observed in both the striatum and substantia nigra regions [27]. Moreover, GDNF-expressing macrophages could successfully cross the BBB and deliver GDNF into the neuro-generated DA neurons after systemic administration [28].
Finally, other cells, such as fibroblasts, were also used as vectors to deliver NTFs. Specifically, fibroblasts modified to express BDNF were inoculated into SCI sites in rats, and these caused regenerative and sprouting responses at the sites of injury [97][98][99]. Similarly, genetically modified baby hamster kidney (BHK) cells and primary cells expressing NGF showed that they were able to rescue cholinergic function in damaged neurons in ageing models of both rodents and non-human primates [100][101][102]. More interestingly, the implanted cells maintained NGF secretion for at least 8 months in primate brains and did not cause the adverse side effects observed in studies with direct administration [103][104][105].
To date, research advances in cell-based therapies offer promising methods for treating neurodegenerative diseases. Although much work remains to be done, the increasing focus on preclinical studies and the recent translation of some of these therapies into clinical trials have paved the way for further progress. The use of modified cells expressing NTFs is likely to play a key role in future clinical strategies to treat neurodegenerative diseases by replacing dysfunctional neurons and providing neuroprotective functions. As mentioned earlier, a potential drawback that remains today is the biosafety.

4. Viral Delivery of Neurotrophic Factors

Viral vector-mediated gene delivery might be a more optimal approach instead of the techniques that have been previously described. Virus administration would permanently alter the cells’ ability to make its own NTF, requiring a single injection at the site of administration, rather than multiple injections [106][107][108][109], and eliminating the cumbersome cell preparation associated with the cell transfer technique [29][31][32][33][35][106][107][108][109][110].
Nakajima et al. [29] reported that injection of adenovirus (AV)-BDNF into bilateral sternomastoid muscles transferred vectors to the damaged sites, via retrograde transport using spinal accessory motor neurons, in SCI rats. The AV-BDNF was able to reach the spinal cord and reduce apoptotic signalling in neurons and oligodendrocytes [29]. Likewise, the application of retrograde AV-BDNF in bilateral sternomastoid muscles of chronically compressed SCI mice led to the recovery of oligodendrocyte progenitors and neurofilament expression via the axons of spinal accessory nerves [31]. However, there are some drawbacks using AV vectors, including immunogenicity, replicability, and the small insertion size of the vectors [29][31].
To date, adeno-associated virus (AAV)-mediated gene transfer of GDNF has been used and evaluated in a number of studies in rodents and primates, particularly for PD [109], HD [106][107], and SCI [32]. Eslamboli et al. [109] showed that unilateral intrastriatal injection of AAV-GDNF, resulting in the expression of high levels of GDNF in the striatum, induced a significant bilateral increase in tyrosine hydroxylase protein levels and DA turnover in a 6-OHDA lesion in marmosets. In addition, AAV-GDNF-treated rats scored better on a blinded semi-quantitative neurological scale compared to rats receiving the control AAV- Green Fluorescent Protein (GFP), which was supported by histological analyses [107]. Interestingly, Fouad et al. [32] reported that rats, with complete thoracic SCI, that received combined treatment, including self-complementary AAV-BDNF and NT-3 administration in the spinal cord, showed not only improved axonal regeneration, but also improved motor function of the hind limbs [32]. AAV vectors offer many of the same advantages as AV vectors, including a wide host-cell range and a relatively high transduction efficiency. In addition, AAV vectors do not express their own proteins and, therefore, would not elicit an immune response, making the technique even more attractive. However, the major drawback is the limited cloning capacity of the vector, which restricts its use in the gene delivery of large genes [32][106][107][109].
Next to AV- and AAV- mediated NTF delivery, viral delivery of GDNF by lentivirus (LV) reversed motor deficits and prevented nigrostriatal degeneration in MPTP-treated monkeys [110]. The delivery of LV expressing GDNF to AD mice models enhanced learning and memory function, while simultaneously improving the cognition capacity [33]. In addition, the group of Pereira de Almeida et al. [111][112] conducted two studies using tetracycline-regulated LV-mediated delivery of CNTF in a quinolinic acid (QA) rat model of HD. The 2001 study [111] showed that the extent of striatal damage was significantly reduced in the CNTF-treated rats, and the volume of the lesion was significantly reduced [111]. In 2002, they reported CNTF′s dose-dependent effects [112]. Remarkably, LV-based administration has numerous advantages, such as long-term transgene expression, low inflammation rate, and large-size gene insertion [34][35][113]. Despite these advantages, in some cases, oncogenic mutation may occur after integration of the LV gene into the host cell genome. This is cited as the main concern of safety in in vivo conditions.

5. Biomaterials to Deliver Neurotrophic Factors

Several of the above-mentioned strategies to deliver NTF to the site of injury in the spinal cord or brain, such as direct delivery, genetically engineered cells, and viral vectors, have a number of drawbacks, including viral vector spread beyond the target area, uncontrolled transgene expression, and immune rejection of transplanted cells. Therefore, there is a growing interest in using biomaterials as vehicles to deliver NTFs. Natural biomaterials are biocompatible, biodegradable, have remodelling advantages and a lower toxicity rate [114], while synthetic biomaterials have a more favourable mechanical and thermal resistance, no immune response capacity, and can be produced on large scales [36][37].
A recent study by Zhijiang et al. [114] used the natural biomaterial methylcellulose (MC), combined with hyaluronic acid (HAMC) hydrogel modified with the peptide KAFAK-LAARLYRKALARQLGVAA (KAFAK) and BDNF. They injected these into a lesion area of SCI rats and showed that locomotor function and axonal regeneration improved 8 weeks after SCI [114]. A similar study with NT-3 also showed that HAMC could release NT-3 for 28 days. The persistence of NT-3 in the target areas confirmed the regeneration and expansion of axons, without induction of the astroglial response, which can cause an inflammatory reaction [38]. Furthermore studies have used other natural bio-materials, such as bioactive scaffolds, to create a microenvironment conducive to endogenous regeneration of neuronal tissue in the SCI site. In particular, gelatin sponge scaffold, silk fibroin, chitosan, or a more developed multichannel nanofibrous gelatin scaffold have been used. These scaffolds were integrated into NT-3, with or without NSCs [43], adipose-derived stem cells [42], or MSCs [44][115]. The in vivo experiments have significantly improved neuronal differentiation, synaptic connection, and axonal remyelination, with reduced local inflammation at the SCI sites following bioactive scaffold implantation with NT-3. In addition the treatment has shown significant improvement in locomotor functionality [39][42][43][44][115].
Poly-lactide-co-glycolide (PLG) is one of the most frequently used synthetic biomaterials for drug delivery, due to its controlled and sustained release properties, low toxicity, and biocompatibility with tissue and cells [45][46]. PLG has been widely used as a material for spinal cord repair or peripheral nerve conduits [46]. Khalin et al. found that iv injection of poloxamer 188 (PX)-coated PLG nanoparticles with BDNF (PLG-BDNF) in TBI mice restored cognition and showed that this system is eligible to cross the BBB and deliver BDNF into the brain of the TBI model [37]. Furthermore, several studies with PLG-BDNF in animal models of SCI observed robust axon growth and remyelination 6 months after initial injury [38][46][47]. These positive findings of PLG-BDNF were not confirmed with CNTF. The latter would not be sufficient in vivo to promote oligodendrocyte remyelination in the glial-depleted environment of unilateral ethidium bromide lesions [48]. Similar to the PLG-BDNF results in SCI rats, poly N-isopropylacrylamide (PNIPAAm) with BDNF improved the axonal regeneration in SCI rats [36]. Finally, intrathecal infusion of N-terminal pegylated (PEG) BDNF (PEG-BDNF) was also used in an attempt to increase NTF release [116]. The authors showed that the PEG-BDNF was able to reach the spinal cord and that its expression was induced in that area. However, they could not observe an improved axonal response or recovery of motor function, which suggests that the amount of BDNF was insufficient [116].
As mentioned earlier, most NTFs have difficulties passing through the BBB and are, therefore, delivered directly into the brain in animal models and some clinical trials with patients using expensive and risky intracranial surgery [69][70][71]. The efficiency of delivery and the poor distribution of some NTFs in the brain are considered the main problems behind their modest effects in clinical trials. There is a great need for NTFs that can be administered systemically to avoid intracranial surgery. Nanoparticles (NPs) can be used to stabilise NTFs and facilitate their transport through the BBB [117]. For example, one study used plasmid DNA NPs encoding human GDNF (pGDNF) that were administered IN to a rat model of PD [118]. The amphetamine-induced rotational behaviour was reduced, and dopaminergic fibre density and cell counts in the lesioned substantia nigra and nerve terminal density in the lesioned striatum were significantly preserved in rats given IN pGDNF [118].

References

  1. Metcalfe, S.M.; Bickerton, S.; Fahmy, T. Neurodegenerative Disease: A Perspective on Cell-Based Therapy in the New Era of Cell-Free Nano-Therapy. Curr. Pharm. Des. 2017, 23, 776–783.
  2. Lindvall, O.; Kokaia, Z. Stem cells in human neurodegenerative disorders—Time for clinical translation? J. Clin. Investig. 2010, 120, 29–40.
  3. Przedborski, S.; Vila, M.; Jackson-Lewis, V. Series Introduction: Neurodegeneration: What is it and where are we? J. Clin. Investig. 2003, 111, 3–10.
  4. Havard Neuro Discovery Center. The Challenge of Neurodegenerative Diseases in an Aging Population. Trends Sci. 2017, 22, 6_92–6_93.
  5. Volkman, R.; Offen, D. Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases. Stem Cells 2017, 35, 1867–1880.
  6. Frozza, R.L.; Lourenco, M.V.; de Felice, F.G. Challenges for Alzheimer’s disease therapy: Insights from novel mechanisms beyond memory defects. Front. Neurosci. 2018, 12, 37.
  7. Ebrahimi, Z.; Talaei, S.; Aghamiri, S.; Goradel, N.H.; Jafarpour, A.; Negahdari, B. Overcoming the blood-brain barrier in neurodegenerative disorders and brain tumours. IET Nanobiotechnology 2020, 14, 441–448.
  8. Zlokovic, B.V. The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders. Neuron 2008, 57, 178–201.
  9. Weil, Z.M.; Norman, G.J.; Devries, A.C.; Nelson, R.J. The Injured Nervous System: A Darwinian Perspective. Prog. Neurobiol. 2008, 86, 48–59.
  10. y Cajal, S.R. Cajal’s Degeneration and Regeneration of the Nervous System; Oxford University Press: Oxford, UK, 1991.
  11. Gianvito, M. How the brain repairs itself: New therapeutic strategies in inflammatory and degenerative CNS disorders. Lancet Neurol. 2004, 3, 372–378.
  12. Fawcett, J.W. The Paper that Restarted Modern Central Nervous System Axon Regeneration Research. Trends Neurosci. 2018, 41, 239–242.
  13. Monje, M.L.; Toda, H.; Palmer, T.D. Inflammatory Blockade Restores Adult Hippocampal Neurogenesis. Science 2003, 302, 1760–1765.
  14. Kerschensteiner, M.; Raineteau, O.; Mettenleiter, T.C.; Schwab, M.E. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 2004, 7, 269–277.
  15. Jessberger, S. Neural repair in the adult brain. F1000 Res. 2016, 5, 169.
  16. Maria, A.; Unit, T.; Raffaele, S. Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage. Ann. Neurol. 2002, 51, 330–339.
  17. Mews, I.; Bergmann, M.; Bunkowski, S.; Gullotta, F.; Brück, W. Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult. Scler. 1998, 4, 55–62.
  18. Vaka, S.R.K.; Sammeta, S.M.; Day, L.B.; Murthy, S.N. Delivery of nerve growth factor to brain via intranasal administration and enhancement of brain uptake. J. Pharm. Sci. 2009, 98, 3640–3646.
  19. Tian, L.; Guo, R.; Yue, X.; Lv, Q.; Ye, X.; Wang, Z.; Chen, Z.; Wu, B.; Xu, G.; Liu, X. Intranasal administration of nerve growth factor ameliorate β-amyloid deposition after traumatic brain injury in rats. Brain Res. 2012, 1440, 47–55.
  20. Braschi, C.; Capsoni, S.; Narducci, R.; Poli, A. Intranasal delivery of BDNF rescues memory deficits in AD11 mice and reduces brain microgliosis. Aging Clin. Exp. Res. 2021, 33, 1223–1238.
  21. Pollock, K.; Dahlenburg, H.; Nelson, H.; Fink, K.D.; Cary, W.; Hendrix, K.; Annett, G.; Torrest, A.; Deng, P.; Gutierrez, J.; et al. Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington’s disease mouse models. Mol. Ther. 2016, 24, 965–977.
  22. Mendes-Pinheiro, B.; Teixeira, F.G.; Anjo, S.I.; Manadas, B.; Behie, L.A.; Salgado, A.J. Secretome of Undifferentiated Neural Progenitor Cells Induces Histological and Motor Improvements in a Rat Model of Parkinson’s Disease. Stem Cells Transl. Med. 2018, 7, 829–838.
  23. Thomsen, G.M.; Avalos, P.; Ma, A.A.; Alkaslasi, M.; Cho, N.; Wyss, L.; Vit, J.P.; Godoy, M.; Suezaki, P.; Shelest, O.; et al. Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis. Stem Cells 2018, 36, 1122–1131.
  24. Suzuki, M.; McHugh, J.; Tork, C.; Shelley, B.; Klein, S.M.; Aebischer, P.; Svendsen, C.N. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection muscule, in a rat model of familial ALS. PLoS ONE 2007, 2, e689.
  25. Gao, X.; Deng, L.; Wang, Y.; Yin, L.; Yang, C.; Du, J.; Yuan, Q. GDNF Enhances Therapeutic Efficiency of Neural Stem Cells-Based Therapy in Chronic Experimental Allergic Encephalomyelitis in Rat. Stem Cells Int. 2016, 2016, 1431349.
  26. Khazaei, M.; Ahuja, C.S.; Nakashima, H.; Nagoshi, N.; Li, L.; Wang, J.; Chio, J.; Badner, A.; Seligman, D.; Ichise, A.; et al. GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents. Sci. Transl. Med. 2020, 12, eaau3538.
  27. Biju, K.; Zhou, Q.; Li, G.; Imam, S.Z.; Roberts, J.L.; Morgan, W.W.; Clark, R.A.; Li, S. Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: A therapeutic strategy for parkinson’s disease. Mol. Ther. 2010, 18, 1536–1544.
  28. Zhao, Y.; Haney, M.J.; Gupta, R.; Bohnsack, J.P.; He, Z.; Kabanov, A.V.; Batrakova, E.V. GDNF-transfected macrophages produce potent neuroprotective effects in parkinson’s disease mouse model. PLoS ONE 2014, 9, e106867.
  29. Nakajima, H.; Uchida, K.; Yayama, T.; Kobayashi, S.; Guerrero, A.R.; Furukawa, S.; Baba, H. Targeted retrograde gene delivery of brain-derived neurotrophic factor suppresses apoptosis of neurons and oligodendroglia after spinal cord injury in rats. Spine 2010, 35, 497–504.
  30. Hovland, D.N.; Boyd, R.B.; Butt, M.T.; Engelhardt, J.A.; Moxness, M.S.; Ma, M.H.; Emery, M.G.; Ernst, N.B.; Reed, R.P.; Zeller, J.R.; et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys. Toxicol. Pathol. 2007, 35, 676–692.
  31. Uchida, K.; Nakajima, H.; Hirai, T.; Yayama, T.; Chen, K.; Guerrero, A.R.; Johnson, W.E.; Baba, H. The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice. Spine 2012, 37, 2125–2135.
  32. Fouad, K.; Bennett, D.J.; Vavrek, R.; Blesch, A. Long-term viral brain-derived neurotrophic factor delivery promotes spasticity in rats with a cervical spinal cord hemisection. Front. Neurol. 2013, 4, 187.
  33. Revilla, S.; Ursulet, S.; Álvarez-López, M.J.; Castro-Freire, M.; Perpiñá, U.; García-Mesa, Y.; Bortolozzi, A.; Giménez-Llort, L.; Kaliman, P.; Cristòfol, R.; et al. Lenti-GDNF Gene Therapy Protects Against Alzheimer’s Disease-Like Neuropathology in 3xTg-AD Mice and MC65 Cells. CNS Neurosci. Ther. 2014, 20, 961–972.
  34. Popovic, N.; Maingay, M.; Kirik, D.; Brundin, P. Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes. Exp. Neurol. 2005, 193, 65–74.
  35. Humbel, M.; Ramosaj, M.; Zimmer, V.; Regio, S.; Aeby, L.; Moser, S.; Boizot, A.; Sipion, M.; Rey, M.; Déglon, N. Maximizing lentiviral vector gene transfer in the CNS. Gene Ther. 2021, 28, 75–88.
  36. Conova, L.; Vernengo, J.; Jin, Y.; Himes, B.T.; Neuhuber, B.; Fischer, I.; Lowman, A. A pilot study of poly(N-isopropylacrylamide)-g-polyethylene glycol and poly(N-isopropylacrylamide)-g-methylcellulose branched copolymers as injectable scaffolds for local delivery of neurotrophins and cellular transplants into the injured spinal cord: Lab. J. Neurosurg. Spine 2011, 15, 594–604.
  37. Khalin, I.; Alyautdin, R.; Wong, T.W.; Gnanou, J.; Kocherga, G.; Kreuter, J. Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury. Drug Deliv. 2016, 23, 3520–3528.
  38. Donaghue, I.E.; Tator, C.H.; Shoichet, M.S. Sustained delivery of bioactive neurotrophin-3 to the injured spinal cord. Biomater. Sci. 2015, 3, 65–72.
  39. Li, G.; Che, M.T.; Zeng, X.; Qiu, X.C.; Feng, B.; Lai, B.Q.; Shen, H.Y.; Ling, E.A.; Zeng, Y.S. Neurotrophin-3 released from implant of tissue-engineered fibroin scaffolds inhibits inflammation, enhances nerve fiber regeneration, and improves motor function in canine spinal cord injury. J. Biomed. Mater. Res.—Part A 2018, 106, 2158–2170.
  40. McMurran, C.E.; Zhao, C.; Franklin, R.J.M. Toxin-based models to investigate demyelination and remyelination. Methods Mol. Biol. 2019, 1936, 377–396.
  41. Moloney, T.C.; Rooney, G.E.; Barry, F.P.; Howard, L.; Dowd, E. Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain. Brain Res. 2010, 1359, 33–43.
  42. Ji, W.C.; Li, M.; Jiang, W.T.; Ma, X.; Li, J. Protective effect of brain-derived neurotrophic factor and neurotrophin-3 overexpression by adipose-derived stem cells combined with silk fibroin/chitosan scaffold in spinal cord injury. Neurol. Res. 2020, 42, 361–371.
  43. Sun, X.; Zhang, C.; Xu, J.; Zhai, H.; Liu, S.; Xu, Y.; Hu, Y.; Long, H.; Bai, Y.; Quan, D. Neurotrophin-3-Loaded Multichannel Nanofibrous Scaffolds Promoted Anti-Inflammation, Neuronal Differentiation, and Functional Recovery after Spinal Cord Injury. ACS Biomater. Sci. Eng. 2020, 6, 1228–1238.
  44. Oudega, M.; Hao, P.; Shang, J.; Haggerty, A.E.; Wang, Z.; Sun, J.; Liebl, D.J.; Shi, Y.; Cheng, L.; Duan, H.; et al. Validation study of neurotrophin-3-releasing chitosan facilitation of neural tissue generation in the severely injured adult rat spinal cord. Exp. Neurol. 2019, 312, 51–62.
  45. Makadia, H.K.; Siegel, S.J. Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 2011, 3, 1377–1397.
  46. Smith, D.R.; Dumont, C.M.; Ciciriello, A.J.; Guo, A.; Tatineni, R.; Munsell, M.K.; Cummings, B.J.; Anderson, A.J.; Shea, L.D. PLG Bridge Implantation in Chronic SCI Promotes Axonal Elongation and Myelination. ACS Biomater. Sci. Eng. 2019, 5, 6679–6690.
  47. Tuinstra, H.M.; Aviles, M.O.; Shin, S.; Holland, S.J.; Zelivyanskaya, M.L.; Fast, A.G.; Ko, S.Y.; Margul, D.J.; Bartels, A.K.; Boehler, R.M.; et al. Multifunctional, multichannel bridges that deliver neurotrophin encoding lentivirus for regeneration following spinal cord injury. Biomaterials 2012, 33, 1618–1626.
  48. Talbott, J.F.; Cao, Q.; Bertram, J.; Nkansah, M.; Benton, R.L.; Lavik, E.; Whittemore, S.R. CNTF promotes the survival and differentiation of adult spinal cord-derived oligodendrocyte precursor cells in vitro but fails to promote remyelination in vivo. Exp. Neurol. 2007, 204, 485–489.
  49. Sun, S.; Zhang, Q.; Li, M.; Gao, P.; Huang, K.; Beejadhursing, R.; Jiang, W.; Lei, T.; Zhu, M.; Shu, K. GDNF Promotes Survival and Therapeutic Efficacy of Human Adipose-Derived Mesenchymal Stem Cells in a Mouse Model of Parkinson’s Disease. Cell Transplant. 2020, 29, 0963689720908512.
  50. Suzuki, M.; McHugh, J.; Tork, C.; Shelley, B.; Hayes, A.; Bellantuono, I.; Aebischer, P.; Svendsen, C.N. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol. Ther. 2008, 16, 2002–2010.
  51. Abbaszadeh, H.A.; Tiraihi, T.; Noori-Zadeh, A.; Delshad, A.R.; Sadeghizade, M.; Taheri, T. Human ciliary neurotrophic factor-overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury. Cytotherapy 2015, 17, 912–921.
  52. Zhang, W.; Yan, Q.; Zeng, Y.; Zhang, X.; Xiong, Y.; Wang, J.; Chen, S. Implantation of adult bone marrow-derived mesenchymal stem cells transfected with the neurotrophin-3 gene and pretreated with retinoic acid in completely transected spinal cord. Brain Res. 2010, 1359, 256–271.
  53. Gransee, H.M.; Zhan, W.Z.; Sieck, G.C.; Mantilla, C.B. Localized delivery of brain-derived neurotrophic factor-expressing mesenchymal stem cells enhances functional recovery following cervical spinal cord injury. J. Neurotrauma 2015, 32, 185–193.
  54. Lu, Z.; Hu, X.; Zhu, C.; Wang, D.; Zheng, X.; Liu, Q. Overexpression of CNTF in Mesenchymal Stem Cells reduces demyelination and induces clinical recovery in experimental autoimmune encephalomyelitis mice. J. Neuroimmunol. 2009, 206, 58–69.
  55. Cedarbaum, J.M.; Chapman, C.; Charatan, M.; Stambler, N.; Andrews, L.; Zhan, C.; Radka, S.; Morrisey, D.; Lakings, D.; Brooks, B.R.; et al. A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. Clin. Neuropharmacol. 1995, 18, 515–532.
  56. Bongioanni, P.; Reali, C.; Sogos, V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst. Rev. 2004, 2004, CD004302.
  57. Lang, A.E.; Gill, S.; Patel, N.K.; Lozano, A.; Nutt, J.G.; Penn, R.; Brooks, D.J.; Hotton, G.; Moro, E.; Heywood, P.; et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 2006, 59, 459–466.
  58. Emerich, D.F.; Lindner, M.D.; Winn, S.R.; Chen, E.Y.; Frydel, B.R.; Kordower, J.H. Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington’s disease. J. Neurosci. 1996, 16, 5168–5181.
  59. Mittoux, V.; Joseph, J.M.; Conde, F.; Palfi, S.; Dautry, C.; Poyot, T.; Bloch, J.; Deglon, N.; Ouary, S.; Nimchinsky, E.A.; et al. Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington’s disease. Hum. Gene Ther. 2000, 11, 1177–1187.
  60. Bachoud-Lévi, A.C.; Déglon, N.; Nguyen, J.P.; Bloch, J.; Bourdet, C.; Winkel, L.; Rémy, P.; Goddard, M.; Lefaucheur, J.P.; Brugières, P.; et al. Neuroprotective gene therapy for Huntington’s disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum. Gene Ther. 2000, 11, 1723–1729.
  61. Aebischer, P.; Schluep, M.; Déglon, N.; Joseph, J.M.; Hirt, L.; Heyd, B.; Goddard, M.; Hammang, J.P.; Zurn, A.D.; Kato, A.C.; et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat. Med. 1996, 2, 696–699.
  62. Tuszynski, M.H.; Thal, L.; Pay, M.; Salmon, D.P.; U, H.S.; Bakay, R.; Patel, P.; Blesch, A.; Vahlsing, H.L.; Ho, G.; et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 2005, 11, 551–555.
  63. Hadaczek, P.; Eberling, J.L.; Pivirotto, P.; Bringas, J.; Forsayeth, J.; Bankiewicz, K.S. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol. Ther. 2010, 18, 1458–1461.
  64. Tuszynski, M.H.; Yang, J.H.; Barba, D.; Hoi-Sang, U.; Bakay, R.A.E.; Pay, M.M.; Masliah, E.; Conner, J.M.; Kobalka, P.; Roy, S.; et al. Nerve growth factor gene therapy activation of neuronal responses in Alzheimer disease. JAMA Neurol. 2015, 72, 1139–1147.
  65. Cedarbaum, J.M.; Chapman, C.; Charatan, M.T.; Stambler, N.; Andrews, L.; Zhan, C.; Radka, S.; Morrisey, D.; Lakings, D.; Brooks, B.R.; et al. The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: Relation to parameters of the acute-phase response. Clin. Neuropharmacol. 1995, 18, 500–514.
  66. Cedarbaum, J.M.; Brooks, B.R. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996, 46, 1244–1249.
  67. Miller, R.G.; Petajan, J.H.; Bryan, W.W.; Armon, C.; Barohn, R.J.; Goodpasture, J.C.; Hoagland, R.J.; Parry, G.J.; Ross, M.A.; Stromatt, S.C. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Ann. Neurol. 1996, 39, 256–260.
  68. Miller, R.G.; Bryan, W.W.; Dietz, M.A.; Munsat, T.L.; Petajan, J.H.; Smith, S.A.; Goodpasture, J.C. Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis. Neurology 1996, 47, 1329–1331.
  69. Kordower, J.H.; Palfi, S.; Chen, E.Y.; Ma, S.Y.; Sendera, T.; Cochran, E.J.; Mufson, E.J.; Penn, R.; Goetz, C.G.; Comella, C.D. Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann. Neurol. 1999, 46, 419–424.
  70. Nutt, J.G.; Burchiel, K.J.; Comella, C.L.; Jankovic, J.; Lang, A.E.; Laws, E.R.; Lozano, A.M.; Penn, R.D.; Simpson, R.K.; Stacy, M.; et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003, 60, 69–73.
  71. Gill, S.S.; Patel, N.K.; Hotton, G.R.; O’Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D.J.; Svendsen, C.N.; Heywood, P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 2003, 9, 589–595.
  72. Patel, N.K.; Bunnage, M.; Plaha, P.; Svendsen, C.N.; Heywood, P.; Gill, S.S. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: A two-year outcome study. Ann. Neurol. 2005, 57, 298–302.
  73. Weissmiller, A.M.; Wu, C. Current advances in using neurotrophic factors to treat neurodegenerative disorders. Transl. Neurodegener. 2012, 1, 14.
  74. Oliveira, S.L.B.; Pillat, M.M.; Cheffer, A.; Lameu, C.; Schwindt, T.T.; Ulrich, H. Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytom. Part A 2013, 83A, 76–89.
  75. Pietrucha-Dutczak, M.; Amadio, M.; Govoni, S.; Lewin-Kowalik, J.; Smedowski, A. The role of endogenous neuroprotective mechanisms in the prevention of retinal ganglion cells degeneration. Front. Neurosci. 2018, 12, 834.
  76. Lapchak, P.A.; Jiao, S.; Collins, F.; Miller, P.J. Glial cell line-derived neurotrophic factor: Distribution and pharmacology in the rat following a bolus intraventricular injection. Brain Res. 1997, 747, 92–102.
  77. Martin, D.; Miller, G.; Fischer, N.; Dix, D.; Cullen, T.; Russell, D. Glial Cell Line-derived Neurotrophic Factor: The Lateral Cerebral Ventricle as a Site of Administration for Stimulation of the Substantia Nigra Dopamine System in Rats. Eur. J. Neurosci. 1996, 8, 1249–1255.
  78. Bowenkamp, K.E.; Lapchak, P.A.; Hoffer, B.J.; Miller, P.J.; Bickford, P.C. Intracerebroventricular glial cell line-derived neurotrophic factor improves motor function and supports nigrostriatal dopamine neurons in bilaterally 6-hydroxydopamine lesioned rats. Exp. Neurol. 1997, 145, 104–117.
  79. Lapchak, P.A.; Miller, P.J.; Collins, F.; Jiao, S. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: Comparison of intraventricular and intranigral delivery. Neuroscience 1997, 78, 61–72.
  80. Jönhagen, M.E.; Nordberg, A.; Amberla, K.; Bäckman, L.; Ebendal, T.; Meyerson, B.; Olson, L.; Seiger, Å.; Shigeta, M.; Theodorsson, E.; et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 1998, 9, 246–257.
  81. Williams, L.R. Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Exp. Neurol. 1991, 113, 31–37.
  82. Isaacson, L.G.; Saffran, B.N.; Crutcher, K.A. Intracerebral NGF infusion induces hyperinnervation of cerebral blood vessels. Neurobiol. Aging 1990, 11, 51–55.
  83. Greg, A.; Gerhardt, A.; Wayne, A.; Huett, P. GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys. Brain Res. 1999, 817, 163–171.
  84. Sergio, C.M.; Iravani, M. Glial cell line-derived neurotrophic factor concentration dependently improves disability and motor activity in MPTP-treated common marmosets. Eur. J. Pharmacol. 2001, 412, 45–50.
  85. Lapchak, P.A. Topographical distribution of w 125 I x -glial cell line-derived neurotrophic factor in unlesioned and MPTP-lesioned rhesus monkey brain following a bolus intraventricular injection. Brain Res. 1998, 789, 9–22.
  86. Zhang, Z.; Miyoshi, Y.; Lapchak, P.A.; Collins, F.; Hilt, D.; Lebel, C.; Kryscio, R.; Gash, D.M. Dose response to intraventricular glial cell line-derived neurotrophic factor administration in Parkinsonian monkeys. J. Pharmacol. Exp. Ther. 1997, 282, 1396–1401.
  87. Winkler, J.; Ramirez, G.A.; Kuhn, H.G.; Peterson, D.A.; Day-Lollini, P.A.; Stewart, G.R.; Tuszynski, M.H.; Gage, F.H.; Thal, L.J. Reversible schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor. Ann. Neurol. 1997, 41, 82–93.
  88. Tuszynski, M.H. Intraparenchymal NGF infusions rescue degenerating cholinergic neurons. Cell Transplant. 2000, 9, 629–636.
  89. Yi, A.; Markesbery, W.; Zhang, Z.; Grondin, R. Intraputamenal infusion of GDNF in aged rhesus monkeys_ Distribution and dopaminergic effects. J. Comp. Neurol. 2003, 461, 250–261.
  90. Maswood, N.; Grondin, R.; Zhang, Z.; Stanford, J.A.; Surgener, S.P.; Gash, D.M.; Gerhardt, G.A. Effects of chronic intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) in aged Rhesus monkeys. Neurobiol. Aging 2002, 23, 881–889.
  91. Grondin, R.; Zhang, Z.; Yi, A.; Cass, W.A.; Maswood, N.; Andersen, A.H.; Elsberry, D.D.; Klein, M.C.; Gerhardt, G.A.; Gash, D.M. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 2002, 125, 2191–2201.
  92. Poduslo, J.F.; Curran, G.L. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-. Brain Res. Mol. Brain Res. 1996, 36, 280–286.
  93. Blesch, A. Neurotrophic Factors in Neurodegeneration. Brain Pathol. 2006, 16, 295–303.
  94. Sadan, O.; Shemesh, N.; Barzilay, R.; Dadon-Nahum, M.; Blumenfeld-Katzir, T.; Assaf, Y.; Yeshurun, M.; Djaldetti, R.; Cohen, Y.; Melamed, E.; et al. Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: A potential therapy for Huntington’s disease. Exp. Neurol. 2012, 234, 417–427.
  95. Eggenhofer, E.; Luk, F.; Dahlke, M.H.; Hoogduijn, M.J. The life and fate of mesenchymal stem cells. Front. Immunol. 2014, 5, 148.
  96. Makar, T.K.; Bever, C.T.; Singh, I.S.; Royal, W.; Sahu, S.N.; Sura, T.P.; Sultana, S.; Sura, K.T.; Patel, N.; Dhib-Jalbut, S.; et al. Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J. Neuroimmunol. 2009, 210, 40–51.
  97. Tobias, C.A.; Shumsky, J.S.; Shibata, M.; Tuszynski, M.H.; Fischer, I.; Tessler, A.; Murray, M. Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration. Exp. Neurol. 2003, 184, 97–113.
  98. Jin, Y.; Fischer, I.; Tessler, A.; Houle, J.D. Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp. Neurol. 2002, 177, 265–275.
  99. McTigue, D.M.; Horner, P.J.; Stokes, B.T.; Gage, F.H. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J. Neurosci. 1998, 18, 5354–5365.
  100. Tuszynski, M.H.; Roberts, J.; Senut, M.C.; Hs, U.; Gage, F.H. Gene therapy in the adult primate brain: Intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther. 1996, 3, 305–314.
  101. Emerich, D.F.; Winn, S.R.; Harper, J.; Hammang, J.P.; Baetge, E.E.; Kordower, J.H. Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: Rescue and sprouting of degenerating cholinergic basal forebrain neurons. J. Comp. Neurol. 1994, 349, 148–164.
  102. Kordower, J.H.; Winn, S.R.; Liu, Y.T.; Mufson, E.J.; Sladek, J.R.; Hammang, J.P.; Baetge, E.E.; Emerich, D.F. The aged monkey basal forebrain: Rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc. Natl. Acad. Sci. USA 1994, 91, 10898–10902.
  103. Smith, D.E.; Roberts, J.; Gage, F.H.; Tuszynski, M.H. Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc. Natl. Acad. Sci. USA 1999, 96, 10893–10898.
  104. Conner, J.M.; Darracq, M.A.; Roberts, J.; Tuszynski, M.H. Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation. Proc. Natl. Acad. Sci. USA 2001, 98, 1941–1946.
  105. Chen, K.S.; Gage, F.H. Somatic gene transfer of NGF to the aged brain: Behavioral and morphological amelioration. J. Neurosci. 1995, 15, 2819–2825.
  106. Kells, A.P.; Fong, D.M.; Dragunow, M.; During, M.J.; Young, D.; Connor, B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol. Ther. 2004, 9, 682–688.
  107. McBride, J.L.; During, M.J.; Wuu, J.; Chen, E.Y.; Leurgans, S.E.; Kordower, J.H. Structural and functional neuroprotection in a rat model of Huntington’s disease by viral gene transfer of GDNF. Exp. Neurol. 2003, 181, 213–223.
  108. Bankiewicz, K.S.; Forsayeth, J.; Eberling, J.L.; Sanchez-Pernaute, R.; Pivirotto, P.; Bringas, J.; Herscovitch, P.; Carson, R.E.; Eckelman, W.; Reutter, B.; et al. Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC. Mol. Ther. 2006, 14, 564–570.
  109. Eslamboli, A.; Georgievska, B.; Ridley, R.M.; Baker, H.F.; Muzyczka, N.; Burger, C.; Mandel, R.J.; Annett, L.; Kirik, D. Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s disease. J. Neurosci. 2005, 25, 769–777.
  110. Kordower, J.H.; Emborg, M.E.; Bloch, J.; Ma, S.Y.; Chu, Y.; Leventhal, L.; McBride, J.; Chen, E.Y.; Palfi, S.; Roitberg, B.Z.; et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 2000, 290, 767–773.
  111. De Almeida, L.P.; Zala, D.; Aebischer, P.; Déglon, N. Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington’s disease. Neurobiol. Dis. 2001, 8, 433–446.
  112. Régulier, E.; De Almeida, L.P.; Sommer, B.; Aebischer, P.; Déglon, N. Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline- regulated lentiviral vectors in the quinolinic acid rat model of Huntington’ s disease. Hum. Gene Ther. 2002, 13, 1981–1990.
  113. Bensadoun, J.C.; Déglon, N.; Tseng, J.L.; Ridet, J.L.; Zurn, A.D.; Aebischer, P. Lentiviral vectors as a gene delivery system in the mouse midbrain: Cellular and behavioral improvements in a 6-OHDA model of Parkinson’s disease using GDNF. Exp. Neurol. 2000, 164, 15–24.
  114. He, Z.; Zang, H.; Zhu, L.; Huang, K.; Yi, T.; Zhang, S.; Cheng, S. An anti-inflammatory peptide and brain-derived neurotrophic factor-modified hyaluronan-methylcellulose hydrogel promotes nerve regeneration in rats with spinal cord injury. Int. J. Nanomed. 2019, 14, 721–732.
  115. Wu, G.H.; Shi, H.J.; Che, M.T.; Huang, M.Y.; Wei, Q.S.; Feng, B.; Ma, Y.H.; Wang, L.J.; Jiang, B.; Wang, Y.Q.; et al. Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue. Biomaterials 2018, 181, 15–34.
  116. Ankeny, D.P.; McTigue, D.M.; Guan, Z.; Yan, Q.; Kinstler, O.; Stokes, B.T.; Jakeman, L.B. Pegylated brain-derived neurotrophic factor shows improved distribution into the spinal cord and stimulates locomotor activity and morphological changes after injury. Exp. Neurol. 2001, 170, 85–100.
  117. Bondarenko, O.; Saarma, M. Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain. Front. Cell Neurosci. 2021, 15, 682597.
  118. Aly, A.E.E.; Harmon, B.T.; Padegimas, L.; Sesenoglu-Laird, O.; Cooper, M.J.; Waszczak, B.L. Intranasal Delivery of pGDNF DNA Nanoparticles Provides Neuroprotection in the Rat 6-Hydroxydopamine Model of Parkinson’s Disease. Mol. Neurobiol. 2019, 56, 688–701.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Yousra El Ouaamari , Jasper Van den Bos , Barbara Willekens , Nathalie Cools , Inez Wens
View Times: 530
Revisions: 2 times (View History)
Update Date: 10 Mar 2023
Table of Contents
    Notice
    You are not a member of the advisory board for this topic. If you want to update advisory board member profile, please contact office@encyclopedia.pub.
    OK
    Confirm
    Only members of the Encyclopedia advisory board for this topic are allowed to note entries. Would you like to become an advisory board member of the Encyclopedia?
    Yes
    No
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    There is no comment~
    ${ textCharacter }/${ maxCharacter }
    Submit
    Cancel
    ${ selectedItem.replyTextCharacter }/${ selectedItem.replyMaxCharacter }
    Submit
    Cancel
    Confirm
    Are you sure to Delete?
    Yes No
    Academic Video Service
    Feedback