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  1. Article ; Online: Adeno-Associated Virus-Mediated Dorsal Root Ganglion Toxicity in the New Zealand White Rabbit.

    Tien, Eric / Grubor, Branka / Kirkland, Melissa / Chan, Su Jing / van der Munnik, Nick / Xu, Wenlong / Henry, Kate / Hamann, Stefan / Wei, Cong / Lee, Wan-Hung / Gianni, Davide / Brennecke, Ashton / Nambiar, Kalyani / Chen, Jeron / Liu, Bin / Shen, Shen / Tremblay, Claudine / Plowey, Edward D / Trapa, Patrick /
    Fikes, James / Suh, Junghae / Morris, Dale

    Toxicologic pathology

    2024  Volume 52, Issue 1, Page(s) 35–54

    Abstract: Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. ... ...

    Abstract Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal ganglia (TG) has been observed in non-human primates (NHPs) following intravenous (IV) and intrathecal (IT) delivery. Administration of recombinant AAV encoding a human protein transgene via a single intra-cisterna magna (ICM) injection in New Zealand white rabbits resulted in histopathology changes very similar to NHPs: mononuclear cell infiltration, degeneration/necrosis of sensory neurons, and nerve fiber degeneration of sensory tracts in the spinal cord and of multiple nerves. AAV-associated clinical signs and incidence/severity of histologic findings indicated that rabbits were equally or more sensitive than NHPs to sensory neuron damage. Another study using human and rabbit transgene constructs of the same protein demonstrated comparable changes suggesting that the effects are not an immune response to the non-self protein transgene. Rabbit has not been characterized as a species for general toxicity testing of AAV gene therapies, but these studies suggest that it may be an alternative model to investigate mechanisms of AAV-mediated neurotoxicity and test novel AAV designs mitigating these adverse effects.
    MeSH term(s) Animals ; Rabbits ; Ganglia, Spinal ; Dependovirus/genetics ; Genetic Vectors ; Male ; Humans ; Transgenes ; Female ; Sensory Receptor Cells
    Language English
    Publishing date 2024-02-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 841009-4
    ISSN 1533-1601 ; 0192-6233
    ISSN (online) 1533-1601
    ISSN 0192-6233
    DOI 10.1177/01926233241229808
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen.

    Paris, Alessio / Bora, Pranami / Parolo, Silvia / MacCannell, Drew / Monine, Michael / van der Munnik, Nick / Tong, Xiao / Eraly, Satish / Berger, Zdenek / Graham, Danielle / Ferguson, Toby / Domenici, Enrico / Nestorov, Ivan / Marchetti, Luca

    CPT: pharmacometrics & systems pharmacology

    2022  Volume 12, Issue 2, Page(s) 196–206

    Abstract: Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing ...

    Abstract Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen. Physiological changes typical of the pediatric age and the contribution of SMA and its treatment to the peripheral pNfH levels were included in the model by extending the equations of a previously developed mathematical model describing the neurofilament trafficking in healthy adults. All model parameters were estimated by fitting data from clinical trials that enrolled SMA patients treated with nusinersen. The data from the control group of the study was employed to build an in silico population of untreated subjects, and the parameters related to the treatment were estimated by fitting individual pNfH time series of SMA patients followed during the treatment. The final model reproduces well the pNfH levels in the presence of SMA in both the treated and untreated conditions. The results were validated by comparing model predictions with the data obtained from an additional cohort of SMA patients. The reported good predictive model performance makes it a valuable tool for investigating pNfH as a biomarker of disease progression and treatment response in SMA and for the in silico evaluation of novel treatment protocols.
    MeSH term(s) Adult ; Humans ; Child ; Infant, Newborn ; Infant ; Child, Preschool ; Adolescent ; Young Adult ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Intermediate Filaments ; Network Pharmacology ; Muscular Atrophy, Spinal/drug therapy ; Biomarkers
    Chemical Substances nusinersen (5Z9SP3X666) ; Oligonucleotides, Antisense ; Biomarkers
    Language English
    Publishing date 2022-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12890
    Database MEDical Literature Analysis and Retrieval System OnLINE

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