Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in ...Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.展开更多
Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemi...Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.展开更多
Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostas...Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostasis,activation,and proliferation of microglia.Its ligands include CSF1 and interleukin-34 (IL-34).展开更多
Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the rege...Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the regenerative capacity of axotomised neurons is one requirement for successful regeneration. Forty-five years ago, it was reported that crushing of the sciatic nerves of adult mice two weeks before cutting the nerves accelerated the regrowth of their axons （McQuarrie and Grafstein, 1973）. The nerve injury two weeks before triggered the regeneration machinery in the injured neurons, leading to faster axonal regrowth after a subsequent lesion. Later it was found that a lesion to a peripheral nerve also strongly enhanced the regeneration of the central branches of the appropriate primary sensory neurons （Richardson and Issa, 1984）. This phenomenon is termed preconditioning lesion （or conditioning lesion if the central branches of the sensory neurons are injured after a concomitant in- jury to their peripheral branches）.展开更多
基金supported by Scottish Rugby Union,Graham and Pam Dixon,Medical Research Scotland,University of Aberdeen HOTSTART Scholarship Programme(to WH)。
文摘Currently,there is no cure for traumatic spinal co rd injury but one therapeutic approach showing promise is gene therapy.In this systematic review and meta-analysis,we aim to assess the efficacy of gene therapies in pre-clinical models of spinal cord injury and the risk of bias.In this metaanalysis,registe red at PROSPERO(Registration ID:CRD42020185008),we identified relevant controlled in vivo studies published in English by searching the PubMed,Web of Science,and Embase databases.No restrictions of the year of publication were applied and the last literature search was conducted on August 3,2020.We then conducted a random-effects meta-analysis using the restricted maximum likelihood estimator.A total of 71 studies met our inclusion crite ria and were included in the systematic review.Our results showed that overall,gene therapies were associated with improvements in locomotor score(standardized mean difference[SMD]:2.07,95%confidence interval[CI]:1.68-2.47,Tau^(2)=2.13,I^(2)=83.6%)and axonal regrowth(SMD:2.78,95%CI:1.92-3.65,Tau^(2)=4.13,I^(2)=85.5%).There was significant asymmetry in the funnel plots of both outcome measures indicating the presence of publication bias.We used a modified CAMARADES(Collaborative Approach to M eta-Analysis and Review of Animal Data in Experimental Studies)checklist to assess the risk of bias,finding that the median score was 4(IQR:3-5).In particula r,reports of allocation concealment and sample size calculations were lacking.In conclusion,gene therapies are showing promise as therapies for spinal co rd injury repair,but there is no consensus on which gene or genes should be targeted.
基金supported by Scottish Rugby Union funding to WH and DSthe NRB PhD scholarship from the International Spinal Rsesarch Trust to AGBa Hot-Start Scholarship from the University of aberdeen to DD。
文摘Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.
文摘Colony stimulating factor 1 receptor(CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS),which directly controls the homeostasis,activation,and proliferation of microglia.Its ligands include CSF1 and interleukin-34 (IL-34).
文摘Neurons in the central nervous system （CNS） of adult mammals have a weak intrinsic regenerative capacity, which is one contributing factor to the failure of axonal regeneration. Finding the means to elevate the regenerative capacity of axotomised neurons is one requirement for successful regeneration. Forty-five years ago, it was reported that crushing of the sciatic nerves of adult mice two weeks before cutting the nerves accelerated the regrowth of their axons （McQuarrie and Grafstein, 1973）. The nerve injury two weeks before triggered the regeneration machinery in the injured neurons, leading to faster axonal regrowth after a subsequent lesion. Later it was found that a lesion to a peripheral nerve also strongly enhanced the regeneration of the central branches of the appropriate primary sensory neurons （Richardson and Issa, 1984）. This phenomenon is termed preconditioning lesion （or conditioning lesion if the central branches of the sensory neurons are injured after a concomitant in- jury to their peripheral branches）.
