Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord

Wong, Liang‐Fong; Yip, Ping K.; Battaglia, Anna; Grist, John; Corcoran, Jonathan; Maden, Malcolm; Azzouz, Mimoun; Kingsman, Susan M.; Kingsman, Alan J.; Mazarakis, Nicholas D.; McMahon, Stephen B.

doi:10.1038/nn1622

Cited by 116 publications

(85 citation statements)

References 39 publications

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“…The lentiviral vector for delivery of hPGC-1α in our study was well tolerated, did not trigger adverse effects, and allowed sustained expression of the transgene for months. Successful proof-of-principle studies of gene therapy using similarly pseudotyped lentiviral vectors have been demonstrated in animal models of ALS (34,35), spinal muscular atrophy (36), and spinal nerve injury (37). In addition, we have developed and tested a similar vector for dopamine replacement therapy in late stage Parkinson's disease patients in a phase I/II clinical trial, showing long-term expression and improved motor behavior in treated patients (38).…”

Section: Discussionmentioning

confidence: 99%

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Katsouri

Lim

Blondrath

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.Aβ | BACE1 | growth factor | inflammation | neurodegeneration

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Section: Discussionmentioning

confidence: 99%

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Katsouri

Lim

Blondrath

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Viral delivery has been used to deliver integrin receptors and retinoic acid receptors to sensory neurons to enhance axonal growth from the transduced neurons [130,131]. These studies focused on manipulation of the cellular response in neurons that are already able to regenerate; however, a similar approach has also been used to alter the response of the more refractory corticospinal motor neurons.…”

Section: Intrinsic Capacity To Regeneratementioning

confidence: 99%

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

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“…[1][2][3] We have developed vectors based on equine infectious anaemia virus (EIAV) intended for human clinical use to treat diseases including Parkinson's disease, 4,5 motor neuron disease 6 and spinal cord injury. 7 These vectors have been designed to maximize safety but it is also necessary to evaluate safety in appropriate assays. We now report the design and validation of an assay to detect the presence of replication competent lentivirus (RCL) in EIAV vector preparations.…”

Section: Introductionmentioning

confidence: 99%

A replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based lentiviral vectors

et al. 2005

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Lentiviral vectors are being developed to satisfy a wide range of currently unmet medical needs. Vectors destined for clinical evaluation have been rendered multiply defective by deletion of all viral coding sequences and nonessential cis-acting sequences from the transfer genome. The viral envelope and accessory proteins are excluded from the production system. The vectors are produced from separate expression plasmids that are designed to minimize the potential for homologous recombination. These features ensure that the regeneration of the starting virus is impossible. It is a regulatory requirement to confirm the absence of any replication competent virus, so we describe here the development and validation of a replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based vectors. The assay is based on the guidelines developed for testing retroviral vectors, and uses the F-PERT (fluorescent-product enhanced reverse transcriptase) assay to test for the presence of a transmissible reverse transcriptase. We have empirically modelled the replication kinetics of an EIAV-like entity in human cells and devised an amplification protocol by comparison with a replication competent MLV. The RCL assay has been validated at the 20 litre manufacturing scale, during which no RCL was detected. The assay is theoretically applicable to any lentiviral vector and pseudotype combination.

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Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord

Cited by 116 publications

References 39 publications

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

A replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based lentiviral vectors

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