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  1. Artikel: Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases.

    Perez, Barbara A / Shutterly, Alison / Chan, Ying Kai / Byrne, Barry J / Corti, Manuela

    Brain sciences

    2020  Band 10, Heft 2

    Abstract: Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson's disease (PD), and Friedreich's ataxia (FA). ...

    Abstract Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson's disease (PD), and Friedreich's ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.
    Sprache Englisch
    Erscheinungsdatum 2020-02-22
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2651993-8
    ISSN 2076-3425
    ISSN 2076-3425
    DOI 10.3390/brainsci10020119
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity.

    Perez, Barbara A / Shorrock, Hannah K / Banez-Coronel, Monica / Zu, Tao / Romano, Lisa El / Laboissonniere, Lauren A / Reid, Tammy / Ikeda, Yoshio / Reddy, Kaalak / Gomez, Christopher M / Bird, Thomas / Ashizawa, Tetsuo / Schut, Lawrence J / Brusco, Alfredo / Berglund, J Andrew / Hasholt, Lis F / Nielsen, Jorgen E / Subramony, S H / Ranum, Laura Pw

    EMBO molecular medicine

    2021  Band 13, Heft 11, Seite(n) e14095

    Abstract: Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we ... ...

    Abstract Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
    Mesh-Begriff(e) Ataxia ; Humans ; Nerve Tissue Proteins/genetics ; Penetrance ; Proteins ; RNA, Long Noncoding/genetics ; Spinocerebellar Degenerations/genetics ; Trinucleotide Repeat Expansion
    Chemische Substanzen ATXN8 protein, human ; ATXN8OS gene product, human ; Nerve Tissue Proteins ; Proteins ; RNA, Long Noncoding
    Sprache Englisch
    Erscheinungsdatum 2021-10-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.202114095
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.

    Ayhan, Fatma / Perez, Barbara A / Shorrock, Hannah K / Zu, Tao / Banez-Coronel, Monica / Reid, Tammy / Furuya, Hirokazu / Clark, H Brent / Troncoso, Juan C / Ross, Christopher A / Subramony, S H / Ashizawa, Tetsuo / Wang, Eric T / Yachnis, Anthony T / Ranum, Laura Pw

    The EMBO journal

    2018  Band 37, Heft 19

    Abstract: Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in ... ...

    Abstract Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the
    Mesh-Begriff(e) Aging/genetics ; Aging/metabolism ; Aging/pathology ; Animals ; Eukaryotic Initiation Factor-3/genetics ; Eukaryotic Initiation Factor-3/metabolism ; HeLa Cells ; Humans ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Spinocerebellar Degenerations/genetics ; Spinocerebellar Degenerations/metabolism ; Spinocerebellar Degenerations/pathology ; White Matter/metabolism ; White Matter/pathology
    Chemische Substanzen Eukaryotic Initiation Factor-3 ; Nerve Tissue Proteins
    Sprache Englisch
    Erscheinungsdatum 2018-09-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.201899023
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: RAN Translation in Huntington Disease.

    Bañez-Coronel, Monica / Ayhan, Fatma / Tarabochia, Alex D / Zu, Tao / Perez, Barbara A / Tusi, Solaleh Khoramian / Pletnikova, Olga / Borchelt, David R / Ross, Christopher A / Margolis, Russell L / Yachnis, Anthony T / Troncoso, Juan C / Ranum, Laura P W

    Neuron

    2015  Band 88, Heft 4, Seite(n) 667–677

    Abstract: Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, ...

    Abstract Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases.
    Mesh-Begriff(e) Adult ; Aged, 80 and over ; Brain/metabolism ; Case-Control Studies ; Cerebellum/metabolism ; Child ; Female ; Frontal Lobe/metabolism ; HEK293 Cells ; Humans ; Huntingtin Protein ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Male ; Middle Aged ; Neostriatum/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Peptides/metabolism ; Protein Aggregation, Pathological/metabolism ; Protein Biosynthesis ; RNA, Antisense/genetics ; RNA, Antisense/metabolism ; Trinucleotide Repeat Expansion/genetics ; Young Adult
    Chemische Substanzen HTT protein, human ; Huntingtin Protein ; Nerve Tissue Proteins ; Peptides ; RNA, Antisense ; polyalanine (25191-17-7) ; polyleucine (25248-98-0) ; polyserine (25821-52-7) ; polyglutamine (26700-71-0) ; polycysteine (62488-11-3)
    Sprache Englisch
    Erscheinungsdatum 2015-11-18
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2015.10.038
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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