Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein

Chen, Yun‐Hsiang; Wu, Kuo‐Jen; Hsieh, Wei Yuan; Harvey, Brandon K.; Hoffer, Barry J.; Wang, Yun; Yu, Seong‐Jin

doi:10.3390/genes12060948

Cited by 15 publications

(13 citation statements)

References 26 publications

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“…Quite similar approaches to the one described in this publication have been followed by Chen et al (2021) and Butler et al (2022) with AAV-mediated expression of fibril-specific α-synuclein binding nanobodies within the CNS. However, these approaches target intracellular α-synuclein by expression of single-chain intrabodies that are not secreted and that exert protective effects only within actually transduced cells.…”

Section: Discussionmentioning

confidence: 98%

AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies

Duechs

Blazevic

Rechtsteiner

et al. 2022

Preprint

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Prion-like transmission of pathology in alpha-synucleinopathies like Parkinsons disease or multiple system atrophy is increasingly recognized as one potential mechanism to address disease progression. Active and passive immunotherapies targeting insoluble, aggregated alpha-synuclein are already being actively explored in the clinic with mixed outcomes so far. Here, we report the identification of 306C7B3, a highly selective, aggregate-specific alpha-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein. 306C7B3 binding is Ser129-phosphorylation independent and shows high affinity to several different aggregated alpha-synuclein polymorphs, increasing the likelihood that it can also bind to the pathological seeds assumed to drive disease progression in patients. In support of this, highly selective binding to pathological aggregates in postmortem brains of MSA patients was demonstrated, with no staining in samples from other human neurodegenerative diseases. To achieve CNS exposure of 306C7B3, an Adeno-Associated Virus (AAV) based approach driving expression of the secreted antibody within the brain of (Thy-1)-[A30P]-h-alpha-Synuclein mice was used. Widespread central transduction after intrastriatal inoculation was ensured by using the AAV2HBKO serotype, with transduction being spread to areas far away from the inoculation site. Treatment of (Thy-1)-[A30P]-h-alpha-Synuclein mice at the age of 12 months demonstrated significantly increased survival, with 306C7B3 concentration reaching 3.9 nM in the cerebrospinal fluid. These results suggest that AAV-mediated expression of 306C7B3 has great potential as a disease-modifying therapy for alpha-synucleinopathies as it ensures CNS exposure of the antibody, thereby mitigating the selective permeability of the blood-brain barrier.

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Section: Discussionmentioning

confidence: 98%

AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies

Duechs

Blazevic

Rechtsteiner

et al. 2022

Preprint

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“…The N-terminal-targeting AB1 additionally reduced DA and NeuN cell loss [ 110 ]. Very recently Chen and colleagues [ 118 ] (Chen et al, 2021) conducted a preclinical study using a NAC-targeting mAb (NAC32), which showed reduced αsyn pathology in the SN (25%), prevented TH+ neuron degradation and further reduced behavioral deficits [ 118 ]. Targeting monomeric (soluble non-toxic) αsyn proposes a different challenge, as reduction of functional αsyn potentially could harm normal physiological properties.…”

Section: Passive Immunization Strategies In Animal Models and Clinica...mentioning

confidence: 99%

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

et al. 2022

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Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain.

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“…Co-administration of AAV-NAC32 with AAV- α syn to rats, reduced α -syn expression in the substantia nigra and striatum, and spared dopaminergic termini in the striatum. In a rat model of DAT-Cre selective expression of α -syn, nigral injection of AAV-NAC32 diminished α -syn expression, spared nigral dopaminergic neurons, and improved locomotor measurements in open-field monitoring [ 188 ]. Intrabody susceptibility to poor intracellular solubility and a propensity to aggregate can potentially increase the protein burden and neurotoxicity associated with intrabody expression, such as with VH14.…”

Section: Nanobodies As Dmtmentioning

confidence: 99%

Therapeutic Strategies for Immune Transformation in Parkinson’s Disease

Saleh

Marković

Olson

et al. 2022

JPD

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Dysregulation of innate and adaptive immunity can lead to alpha-synuclein (α-syn) misfolding, aggregation, and post-translational modifications in Parkinson’s disease (PD). This process is driven by neuroinflammation and oxidative stress, which can contribute to the release of neurotoxic oligomers that facilitate dopaminergic neurodegeneration. Strategies that promote vaccines and antibodies target the clearance of misfolded, modified α-syn, while gene therapy approaches propose to deliver intracellular single chain nanobodies to mitigate α-syn misfolding, or to deliver neurotrophic factors that support neuronal viability in an otherwise neurotoxic environment. Additionally, transformative immune responses provide potential targets for PD therapeutics. Anti-inflammatory drugs represent one strategy that principally affects innate immunity. Considerable research efforts have focused on transforming the balance of pro-inflammatory effector T cells (Teffs) to favor regulatory T cell (Treg) activity, which aims to attenuate neuroinflammation and support reparative and neurotrophic homeostasis. This approach serves to control innate microglial neurotoxic activities and may facilitate clearance of α-syn aggregates accordingly. More recently, changes in the intestinal microbiome have been shown to alter the gut-immune-brain axis leading to suppressed leakage of bacterial products that can promote peripheral inflammation and α-syn misfolding. Together, each of the approaches serves to interdict chronic inflammation associated with disordered immunity and neurodegeneration. Herein, we examine research strategies aimed at improving clinical outcomes in PD.

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Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein

Cited by 15 publications

References 26 publications

AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies

AAV-mediated Expression of a Novel Conformational Anti-Aggregated α-Synuclein Antibody Prolongs Survival in a Genetic Model of α-Synucleinopathies

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

Therapeutic Strategies for Immune Transformation in Parkinson’s Disease

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