Imperial College London

ProfessorNicholasMazarakis

Faculty of MedicineDepartment of Brain Sciences

Chair MolBioMedicine and Head of Gene Therapy
 
 
 
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Contact

 

+44 (0)20 7594 7024n.mazarakis Website

 
 
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Assistant

 

Mrs Hadeel Abdeen +44 (0)20 7594 7014

 
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Location

 

E402Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

124 results found

Bates REJ, Browne E, Schalks R, Jacobs H, Tan L, Parekh P, Magliozzi R, Calabrese M, Mazarakis ND, Reynolds Ret al., 2022, Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration, Brain: a journal of neurology, Vol: 145, Pages: 4287-4307, ISSN: 0006-8950

Organized meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the CSF of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of lymphotoxin-alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology. Stereotaxic injections of recombinant lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and subpial demyelination that resolved after 28 days, with demyelination being dependent on prior subclinical immunization with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localized overexpression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin + fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial and astroglial activation, subpial demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial demyelination was partially dependent on previous myelin oligodendrocyte glycoprotein immunization, the neuronal loss was present irrespective of immunization. Conditioned medium from LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen

Journal article

Frasca A, Pavlidou E, Bizzotto M, Gao Y, Balestra D, Pinotti M, Dahl HA, Mazarakis ND, Landsberger N, Kinali Met al., 2022, Not Just Loss-of-Function Variations Identification of a Hypermorphic Variant in a Patient With a CDKL5 Missense Substitution, NEUROLOGY-GENETICS, Vol: 8, ISSN: 2376-7839

Journal article

van Olst Y, Rodriguez-Mogeda C, Picon C, Kiljan S, James RE, Kamermans A, van der Pol SMA, Knoop L, Michailidou I, Drost E, Franssen M, Schenk GJ, Geurts JJG, Amor S, Mazarakis ND, van Horssen J, de Vries HE, Reynolds R, Witte MEet al., 2021, Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration, ACTA NEUROPATHOLOGICA, Vol: 141, Pages: 881-899, ISSN: 0001-6322

Journal article

Picon C, Jayaraman A, James R, Beck C, Gallego P, Witte ME, van Horssen J, Mazarakis ND, Reynolds Ret al., 2021, Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter, Acta Neuropathologica, Vol: 141, Pages: 585-604, ISSN: 0001-6322

Sustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meni

Journal article

Pickering CA, Mazarakis ND, 2021, Viral Vector Delivery of DREADDs for CNS Therapy, CURRENT GENE THERAPY, Vol: 21, Pages: 191-206, ISSN: 1566-5232

Journal article

Munoz CP, James R, Jayaraman A, Witte M, Van Horssen J, Mazarakis N, Reynolds Ret al., 2020, Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter, 8th Joint ACTRIMS-ECTRIMS Meeting (MSVirtual), Publisher: SAGE PUBLICATIONS LTD, Pages: 585-585, ISSN: 1352-4585

Conference paper

Gallego-Delgado P, James R, Browne E, Meng J, Umashankar S, Tan L, Picon C, Mazarakis ND, Faisal AA, Howell OW, Reynolds Ret al., 2020, Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier., PLoS Biology, Vol: 18, Pages: 1-36, ISSN: 1544-9173

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.

Journal article

La Montanara P, Hervera A, Baltussen L, Hutson TH, Palmisano I, De Virgiliis F, Gao Y, Bartus K, Majid Q, Gorgoraptis N, Wong K, Downs J, Pizzorusso T, Ultanir S, Leonard H, Yu H, Millar DS, Nagy I, Mazarakis N, Di Giovanni Set al., 2020, Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models, Science Translational Medicine, Vol: 12, Pages: 1-11, ISSN: 1946-6234

Cyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

Journal article

James RE, Schalks R, Browne E, Eleftheriadou I, Munoz CP, Mazarakis ND, Reynolds Ret al., 2020, Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration., Acta Neuropathologica Communications, Vol: 8, Pages: 66-66, ISSN: 2051-5960

Analysis of isolated meninges and cerebrospinal fluid (CSF) of post-mortem MS cases has shown increased gene and protein expression for the pro-inflammatory cytokines: tumour necrosis factor (TNF) and interferon-γ (IFNγ). Here we tested the hypothesis that persistent production of these cytokines in the meningeal compartment and diffusion into underlying GM can drive chronic MS-like GM pathology. Lentiviral transfer vectors were injected into the sagittal sulcus of DA rats to deliver continuous expression of TNF + IFNγ transgenes in the meninges and the resulting neuropathology analysed after 1 and 2 months. Injection of TNF + IFNγ viral vectors, with or without prior MOG immunisation, induced extensive immune cell infiltration (CD4+ and CD8+ T-cells, CD79a + B-cells and macrophages) in the meninges by 28 dpi, which remained at 2 months. Control GFP viral vector did not induce infiltration. Subpial demyelination was seen underlying these infiltrates, which was partly dependant on prior myelin oligodendrocyte glycoprotein (MOG) immunisation. A significant decrease in neuronal numbers was seen at 28 and 56 days in cortical layers II-V that was independent of MOG immunisation. RNA analysis at 28 dpi showed an increase in expression of necroptotic pathway genes, including RIP3, MLKL, cIAP2 and Nox2. PhosphoRIP3+ and phosphoMLKL+ neurons were present in TNF + IFNγ vector injected animals, indicating activation of necroptosis. Our results suggest that persistent expression of TNF in the presence of IFNγ is a potent inducer of meningeal inflammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.

Journal article

Yunan Gao Y, Irvine E, Eleftheriadou I, Naranjo CJ, Hearn-Yeats F, Bosch L, Glegola J, Murdoch L, Czerniak A, Meloni I, Renieri A, Kinali M, Mazarakis NDet al., 2020, Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder, Brain: a journal of neurology, Vol: 143, Pages: 811-832, ISSN: 0006-8950

Cyclin-dependent kinase-like 5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene. It predominantly affects females who typically present with severe early epileptic encephalopathy, global developmental delay, motor dysfunction, autistic features and sleep disturbances. To develop a gene replacement therapy, we initially characterized the human CDKL5 transcript isoforms expressed in the brain, neuroblastoma cell lines, primary astrocytes and embryonic stem cell-derived cortical interneurons. We found that the isoform 1 and to a lesser extent the isoform 2 were expressed in human brain, and both neuronal and glial cell types. These isoforms were subsequently cloned into recombinant adeno-associated viral (AAV) vector genome and high-titre viral vectors were produced. Intrajugular delivery of green fluorescence protein via AAV vector serotype PHP.B in adult wild-type male mice transduced neurons and astrocytes throughout the brain more efficiently than serotype 9. Cdkl5 knockout male mice treated with isoform 1 via intrajugular injection at age 28–30 days exhibited significant behavioural improvements compared to green fluorescence protein-treated controls (1012 vg per animal, n = 10 per group) with PHP.B vectors. Brain expression of the isoform 1 transgene was more abundant in hindbrain than forebrain and midbrain. Transgene brain expression was sporadic at the cellular level and most prominent in hippocampal neurons and cerebellar Purkinje cells. Correction of postsynaptic density protein 95 cerebellar misexpression, a major fine cerebellar structural abnormality in Cdkl5 knockout mice, was found in regions of high transgene expression within the cerebellum. AAV vector serotype DJ efficiently transduced CDKL5-mutant human induced pluripotent stem cell-derived neural progenitors, which were subsequently differentiated into mature neurons. When treating CDKL5-mutant neuro

Journal article

Cencioni MT, Yusuf S, Palmisano I, Lee SB, Ali R, Mazarakis ND, Nicholas R, Costa Frossard L, Villar Guimerans LM, Muraro PAet al., 2019, Soluble CD27 a biomarker of T cell activity in intrathecal inflammation in patients with relapsing-remitting multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 110-111, ISSN: 1352-4585

Conference paper

La Montanara P, Hervera A, Baltussen L, Hutson T, Palmisano I, Palmisano I, De Virgiliis F, Gao Y, Majid Q, Gorgoraptis N, Wong K, Downs J, Di Lazzaro V, Pizzorusso T, Ultanir S, Leonard H, Istvan N, Mazarakis N, Di Giovanni Set al., 2019, Cyclin-dependent-like kinase 5 is required for pain signalling in both human neurons and mouse models, Publisher: bioRxiv

Abstract Cyclin-dependent-like kinase 5 ( Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder. One Sentence Summary Cyclin-dependent-like kinase 5 (Cdkl5) controls nociception in patients and murine models of Cdkl5 deficiency disorder via CaMKII-dependent mechanisms

Working paper

Vlachou V, Larsen L, Pavlidou E, Ismayilova N, Mazarakis ND, Pantazi M, Mankad K, Kinali Met al., 2019, SCN2A mutation in an infant with Ohtahara syndrome and neuroimaging findings: expanding the phenotype of neuronal migration disorders, Journal of Genetics, Vol: 98, ISSN: 0022-1333

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first day of life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.

Journal article

Benger M, Mankad K, Proukakis C, Mazarakis ND, Kinali Met al., 2019, The interaction of genetic mutations in PARK2 and FA2H causes a novel phenotype in a case of childhood-onset movement disorder, Frontiers in Neurology, Vol: 10, ISSN: 1664-2295

Mutations in the PARK2 gene have been implicated in the pathogenesis of early-onset Parkinson's disease. We present a case of movement disorder in a 4-year-old child from consanguineous parents and with a family history of Dopamine responsive dystonia, who was diagnosed with early-onset Parkinson's disease based on initial identification of a pathogenic PARK2 mutation. However, the evolution of the child's clinical picture was unusually rapid, with a preponderance of pyramidal rather than extrapyramidal symptoms, leading to re-investigation of the case with further imaging and genetic sequencing. Interestingly, a second homozygous mutation in the FA2H gene, implicated in Hereditary spastic paraplegia, was revealed, appearing to have contributed to the novel phenotype observed, and highlighting a potential interaction between the two mutated genes.

Journal article

Benger M, Kinali M, Mazarakis N, 2018, Autism spectrum disorder: prospects for treatment using gene therapy, Molecular Autism, Vol: 9, ISSN: 2040-2392

Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy’s potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD.

Journal article

Gao Y, Irvine EE, Eleftheriadou I, Bosch L, Murdoch L, Czerniak A, Glegola JA, James R, Meloni I, Renieri A, Kinali M, Mazarakis NDet al., 2017, Gene therapy with AAV-CDKL5 vectors in models of CDKL5 disorder, European-Society-of-Gene-and-Cell-Therapy (ESCGT) Congress, Publisher: Mary Ann Liebert, Pages: A6-A7, ISSN: 1043-0342

Conference paper

Eleftheriadou I, Dieringer M, Poh XY, Sanchez -Garrido J, Gao Y, Sgourou A, Simmons LE, Mazarakis NDet al., 2017, Selective transduction of astrocytic and neuronal CNS subpopulations by lentiviral vectors pseudotyped with Chikungunya virus envelope, Biomaterials, Vol: 123, Pages: 1-14, ISSN: 1878-5905

Lentiviral vectors are gene delivery vehicles that integrate into the host genome of dividing and non-dividing mammalian cells facilitating long-term transgene expression. Lentiviral vector versatility is greatly increased by incorporating heterologous viral envelope proteins onto the vector particles instead of the native envelope, conferring on these pseudotyped vectors a modified tropism and host range specificity. We investigated the pseudotyping efficiency of HIV-1 based lentiviral vectors with alphaviral envelope proteins from the Chikungunya Virus (CHIKV-G) and Sindbis Virus (SINV-G). Following vector production optimisation, titres for the CHIKV-G pseudotype were comparable to the VSV-G pseudotype but those for the SINV-G pseudotype were significantly lower. High titre CHIKV-G pseudotyped vector efficiently transduced various human and mouse neural cell lines and normal human astrocytes (NHA) in vitro. Although transduction was broad, tropism for NHAs was observed. In vivo stereotaxic delivery in striatum, thalamus and hippocampus respectively in the adult rat brain revealed localised transduction restricted to striatal astrocytes and hippocampal dentate granule neurons. Transduction of different subtypes of granule neurons from precursor to post-mitotic stages of differentiation was evident in the sub-granular zone and dentate granule cell layer. No significant inflammatory response was observed, but comparable to that of VSV-G pseudotyped lentiviral vectors. Robust long-term expression followed for three months post-transduction along with absence of neuroinflammation, coupled to the selective and unique neuron/glial tropism indicates that these vectors could be useful for modelling and gene therapy studies in the CNS.

Journal article

James R, Browne E, Mazarakis ND, Reynolds Ret al., 2016, Lentiviral vector gene transfer of cytokines in the meninges of rats for modeling multiple sclerosis, Conference on Changing the Face of Modern Medicine - Stem Cells and Gene Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A51-A51, ISSN: 1043-0342

Conference paper

Katsouri L, Lim YM, Eleftheriadou I, Mazarakis ND, Sastre Met al., 2016, PGC-1 alpha overexpression by lentiviral vector attenuates amyloid-beta load and neuronal loss in an Alzheimer's disease model, Conference on Changing the Face of Modern Medicine - Stem Cells and Gene Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A27-A27, ISSN: 1043-0342

Conference paper

Katsouri L, Lim YM, Blondrath K, Eleftheriadou I, Lombardero L, Birch AM, Mirzaei N, Irvine EE, Mazarakis N, Sastre Met al., 2016, PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model, Proceedings of the National Academy of Sciences of USA, Vol: 113, Pages: 12292-12297, ISSN: 0027-8424

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.

Journal article

Eleftheriadou I, Manolaras I, Irvine EE, Dieringer M, Trabalza A, Mazarakis NDet al., 2016, αCAR IGF-1 vector targeting of motor neurons ameliorates disease progression in ALS mice, Annals of Clinical and Translational Neurology, Vol: 3, Pages: 752-768, ISSN: 2328-9503

Objective: We have previously described the generation of coxsackievirus andadenovirus receptor (aCAR)-targeted vector, and shown that intramusculardelivery in mouse leg muscles resulted in specific retrograde transduction oflumbar-motor neurons (MNs). Here, we utilized the aCAR-targeted vector toinvestigate the in vivo neuroprotective effects of lentivirally expressed IGF-1 forinducing neuronal survival and ameliorating the neuropathology and behavioralphenotypes of the SOD1G93A mouse model of ALS. Methods: We produced cellfactories of IGF-1 expressing lentiviral vectors (LVs) bearing aCAR or VesicularStomatitis Virus glycoprotein (VSV-G) on their surface so as to compare neuroprotectionfrom MN transduced versus muscle transduced cells. We performedintramuscular delivery of either aCAR IGF-1 or VSVG IGF-1 LVs intokey muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance,coordination and gait analysis were assessed weekly. Results: Weobserved substantial therapeutic efficacy only with the aCAR IGF-1 LV pretreatmentwith up to 50% extension of survival compared to controls. aCAR IGF-1LV-treated animals retained muscle tone and had better motor performanceduring their prolonged survival. Histological analysis of spinal cord samples atend-stage further confirmed that aCAR IGF-1 LV treatment delays disease onsetby increasing MN survival compared with age-matched controls. Intrastriatalinjection of aCAR eGFP LV in rats leads to transduction of neurons and glialocally and neurons in olfactory bulb distally. Interpretation: Our data areindicative of the efficacy of the aCAR IGF-1 LV in this model and support itscandidacy for early noninvasive neuroprotective therapy in ALS.

Journal article

James R, Browne E, Mazarakis N, Reynolds Ret al., 2016, Persistent cytokine production induced in the cerebral meninges in a rat model of MS gives rise to chronic cortical pathology., 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 27-27, ISSN: 1352-4585

Conference paper

Eleftheriadou I, Manolaras I, Irvine E, Mazarakis NDet al., 2015, Neuroprotection in an ALS mouse model following peripheral delivery of motor neuron targeted aCAR-IGF-1 Lentiviral vector, Human Gene Therapy, Vol: 26, Pages: A14-A15, ISSN: 1043-0342

ObjectiveWe have previously described the generation of coxsackievirus and adenovirus receptor (αCAR)-targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar-motor neurons (MNs). Here, we utilized the αCAR-targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF-1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS.MethodsWe produced cell factories of IGF-1 expressing lentiviral vectors (LVs) bearing αCAR or Vesicular Stomatitis Virus glycoprotein (VSV-G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either αCAR IGF-1 or VSVG IGF-1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.ResultsWe observed substantial therapeutic efficacy only with the αCAR IGF-1 LV pretreatment with up to 50% extension of survival compared to controls. αCAR IGF-1 LV-treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end-stage further confirmed that αCAR IGF-1 LV treatment delays disease onset by increasing MN survival compared with age-matched controls. Intrastriatal injection of αCAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.InterpretationOur data are indicative of the efficacy of the αCAR IGF-1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.

Journal article

Browne E, James R, Schalks R, Mazarakis N, Reynolds Ret al., 2015, Chronic lymphotoxin-alpha expression in the meninges produces sub-pial cortical pathology in the rat, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 135-136, ISSN: 1352-4585

Conference paper

James RE, Browne E, Mazarakis N, Reynolds Ret al., 2015, Chronic meningeal production of TNF and interferon-gamma can drive cortical grey matter pathology, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 430-430, ISSN: 1352-4585

Conference paper

Eleftheriadou I, Mazarakis N, 2015, Lentiviral vectors for gene delivery to the nervous system, Gene Delivery and Therapy for Neurological Disorders, Editors: Bo, Verhaagen, Publisher: Humana Press, Pages: 23-66, ISBN: 9781493923052

This volume aims to explore the latest developments in adeno-associated viral and lentiviral vectors as well as the gene therapy strategies for the most common neurological disorders, followed by chapters that include step-by-step guides to ...

Book chapter

Pazarentzos E, Mazarakis ND, 2014, Anticancer Gene Transfer for Cancer Gene Therapy, Anticancer Genes, Editors: Grimm, Publisher: Springer, Pages: 255-280, ISBN: 978-1-4471-6457-9

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field.

Book chapter

Pazarentzos E, Mahul-Mellier A-L, Datler C, Chaisaklert W, Hwang M-S, Kroon J, Qize D, Osborne F, Al-Rubaish A, Al-Ali A, Mazarakis ND, Aboagye EO, Grimm Set al., 2014, I kappa B alpha inhibits apoptosis at the outer mitochondrial membrane independently of NF-kappa B retention, The EMBO Journal, Vol: 33, Pages: 2814-2828, ISSN: 0261-4189

IκBα resides in the cytosol where it retains the inducible transcription factor NF‐κB. We show that IκBα also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF‐κB that accumulate high amounts of mitochondrial IκBα as a NF‐κB target gene. 3T3 IκBα−/− cells also become protected from apoptosis when IκBα is specifically reconstituted at the OMM. Using various IκBα mutants, we demonstrate that apoptosis inhibition and NF‐κB inhibition can be functionally and structurally separated. At mitochondria, IκBα stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When IκBα is reduced in tumour cells with constitutively active NF‐κB, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of IκBα in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF‐κB.

Journal article

Eleftheriadou I, Manolaras I, Trabalza A, Mazarakis NDet al., 2014, Presynaptic NMJ aCAR-targeted Lentiviral Vector for Neuroprotective Gene Therapy in ALS, ESGCT and NVGCT Collaborative Congress, Publisher: MARY ANN LIEBERT, INC, Pages: A82-A83, ISSN: 1043-0342

Conference paper

Eleftheriadou I, Trabalza A, Ellison SM, Gharun K, Mazarakis NDet al., 2014, Specific Retrograde Transduction of Spinal Motor Neurons using Lentiviral Vectors Targeted to Presynaptic NMJ Receptors, MOLECULAR THERAPY, Vol: 22, Pages: 1285-1298, ISSN: 1525-0016

Journal article

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