أعرض في EDS

Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis

التفاصيل البيبلوغرافية
العنوان: Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis
المؤلفون: Kayly Nielsen, Thomas N. Seyfried, Cassie N Bebout, Nathan L. Ta, Douglas R. Martin, Kalajan R Lopez Mercado, Devin E Osterhoudt, Stacy Maitland, Ana Rita Batista, Amanda L. Gross, Heather L. Gray-Edwards, Brandon L. Brunson, Miguel Sena-Esteves
المصدر: Brain : a journal of neurology. 145(2)
سنة النشر: 2020
مصطلحات موضوعية: medicine.medical_specialty, Pathology, Urinary system, Central nervous system, G(M1) Ganglioside, Cerebrospinal fluid, Gangliosides, medicine, Lysosomal storage disease, Animals, Humans, Tissue Distribution, CATS, Ganglioside, Gangliosidosis, GM1, business.industry, Neurodegenerative Diseases, Genetic Therapy, Dependovirus, medicine.disease, beta-Galactosidase, medicine.anatomical_structure, Cats, Quality of Life, Histopathology, Neurology (clinical), Sciatic nerve, business, Biomarkers
الوصف: GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included β-galactosidase and virus distribution, histological analysis and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. β-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.
تدمد: 1460-2156
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d8ed9d67acca2ccb6f478ff3a280934e
https://pubmed.ncbi.nlm.nih.gov/34410345
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....d8ed9d67acca2ccb6f478ff3a280934e
قاعدة البيانات: OpenAIRE
ResultId 1
Header edsair
OpenAIRE
edsair.doi.dedup.....d8ed9d67acca2ccb6f478ff3a280934e
845
3

unknown
844.658874511719
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi.dedup.....d8ed9d67acca2ccb6f478ff3a280934e&custid=s6537998&authtype=sso
FullText Array ( [Availability] => 0 )
Array ( [0] => Array ( [Url] => https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d8ed9d67acca2ccb6f478ff3a280934e# [Name] => EDS - OpenAIRE [Category] => fullText [Text] => View record in OpenAIRE [MouseOverText] => View record in OpenAIRE ) )
Items Array ( [Name] => Title [Label] => Title [Group] => Ti [Data] => Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis )
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Kayly+Nielsen%22">Kayly Nielsen</searchLink><br /><searchLink fieldCode="AR" term="%22Thomas+N%2E+Seyfried%22">Thomas N. Seyfried</searchLink><br /><searchLink fieldCode="AR" term="%22Cassie+N+Bebout%22">Cassie N Bebout</searchLink><br /><searchLink fieldCode="AR" term="%22Nathan+L%2E+Ta%22">Nathan L. Ta</searchLink><br /><searchLink fieldCode="AR" term="%22Douglas+R%2E+Martin%22">Douglas R. Martin</searchLink><br /><searchLink fieldCode="AR" term="%22Kalajan+R+Lopez+Mercado%22">Kalajan R Lopez Mercado</searchLink><br /><searchLink fieldCode="AR" term="%22Devin+E+Osterhoudt%22">Devin E Osterhoudt</searchLink><br /><searchLink fieldCode="AR" term="%22Stacy+Maitland%22">Stacy Maitland</searchLink><br /><searchLink fieldCode="AR" term="%22Ana+Rita+Batista%22">Ana Rita Batista</searchLink><br /><searchLink fieldCode="AR" term="%22Amanda+L%2E+Gross%22">Amanda L. Gross</searchLink><br /><searchLink fieldCode="AR" term="%22Heather+L%2E+Gray-Edwards%22">Heather L. Gray-Edwards</searchLink><br /><searchLink fieldCode="AR" term="%22Brandon+L%2E+Brunson%22">Brandon L. Brunson</searchLink><br /><searchLink fieldCode="AR" term="%22Miguel+Sena-Esteves%22">Miguel Sena-Esteves</searchLink> )
Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => <i>Brain : a journal of neurology</i>. 145(2) )
Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2020 )
Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22medicine%2Emedical%5Fspecialty%22">medicine.medical_specialty</searchLink><br /><searchLink fieldCode="DE" term="%22Pathology%22">Pathology</searchLink><br /><searchLink fieldCode="DE" term="%22Urinary+system%22">Urinary system</searchLink><br /><searchLink fieldCode="DE" term="%22Central+nervous+system%22">Central nervous system</searchLink><br /><searchLink fieldCode="DE" term="%22G%28M1%29+Ganglioside%22">G(M1) Ganglioside</searchLink><br /><searchLink fieldCode="DE" term="%22Cerebrospinal+fluid%22">Cerebrospinal fluid</searchLink><br /><searchLink fieldCode="DE" term="%22Gangliosides%22">Gangliosides</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%22">medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Lysosomal+storage+disease%22">Lysosomal storage disease</searchLink><br /><searchLink fieldCode="DE" term="%22Animals%22">Animals</searchLink><br /><searchLink fieldCode="DE" term="%22Humans%22">Humans</searchLink><br /><searchLink fieldCode="DE" term="%22Tissue+Distribution%22">Tissue Distribution</searchLink><br /><searchLink fieldCode="DE" term="%22CATS%22">CATS</searchLink><br /><searchLink fieldCode="DE" term="%22Ganglioside%22">Ganglioside</searchLink><br /><searchLink fieldCode="DE" term="%22Gangliosidosis%2C+GM1%22">Gangliosidosis, GM1</searchLink><br /><searchLink fieldCode="DE" term="%22business%2Eindustry%22">business.industry</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegenerative+Diseases%22">Neurodegenerative Diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+Therapy%22">Genetic Therapy</searchLink><br /><searchLink fieldCode="DE" term="%22Dependovirus%22">Dependovirus</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edisease%22">medicine.disease</searchLink><br /><searchLink fieldCode="DE" term="%22beta-Galactosidase%22">beta-Galactosidase</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Eanatomical%5Fstructure%22">medicine.anatomical_structure</searchLink><br /><searchLink fieldCode="DE" term="%22Cats%22">Cats</searchLink><br /><searchLink fieldCode="DE" term="%22Quality+of+Life%22">Quality of Life</searchLink><br /><searchLink fieldCode="DE" term="%22Histopathology%22">Histopathology</searchLink><br /><searchLink fieldCode="DE" term="%22Neurology+%28clinical%29%22">Neurology (clinical)</searchLink><br /><searchLink fieldCode="DE" term="%22Sciatic+nerve%22">Sciatic nerve</searchLink><br /><searchLink fieldCode="DE" term="%22business%22">business</searchLink><br /><searchLink fieldCode="DE" term="%22Biomarkers%22">Biomarkers</searchLink> )
Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated. AAV9 expressing feline β-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included β-galactosidase and virus distribution, histological analysis and ganglioside content. Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. β-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity. Restoration of β-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis. )
Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 1460-2156 )
Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d8ed9d67acca2ccb6f478ff3a280934e" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d8ed9d67acca2ccb6f478ff3a280934e</link><br /><link linkTarget="URL" linkTerm="https://pubmed.ncbi.nlm.nih.gov/34410345" linkWindow="_blank">https://pubmed.ncbi.nlm.nih.gov/34410345</link> )
Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN )
Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....d8ed9d67acca2ccb6f478ff3a280934e )
RecordInfo Array ( [BibEntity] => Array ( [Languages] => Array ( [0] => Array ( [Text] => Undetermined ) ) [Subjects] => Array ( [0] => Array ( [SubjectFull] => medicine.medical_specialty [Type] => general ) [1] => Array ( [SubjectFull] => Pathology [Type] => general ) [2] => Array ( [SubjectFull] => Urinary system [Type] => general ) [3] => Array ( [SubjectFull] => Central nervous system [Type] => general ) [4] => Array ( [SubjectFull] => G(M1) Ganglioside [Type] => general ) [5] => Array ( [SubjectFull] => Cerebrospinal fluid [Type] => general ) [6] => Array ( [SubjectFull] => Gangliosides [Type] => general ) [7] => Array ( [SubjectFull] => medicine [Type] => general ) [8] => Array ( [SubjectFull] => Lysosomal storage disease [Type] => general ) [9] => Array ( [SubjectFull] => Animals [Type] => general ) [10] => Array ( [SubjectFull] => Humans [Type] => general ) [11] => Array ( [SubjectFull] => Tissue Distribution [Type] => general ) [12] => Array ( [SubjectFull] => CATS [Type] => general ) [13] => Array ( [SubjectFull] => Ganglioside [Type] => general ) [14] => Array ( [SubjectFull] => Gangliosidosis, GM1 [Type] => general ) [15] => Array ( [SubjectFull] => business.industry [Type] => general ) [16] => Array ( [SubjectFull] => Neurodegenerative Diseases [Type] => general ) [17] => Array ( [SubjectFull] => Genetic Therapy [Type] => general ) [18] => Array ( [SubjectFull] => Dependovirus [Type] => general ) [19] => Array ( [SubjectFull] => medicine.disease [Type] => general ) [20] => Array ( [SubjectFull] => beta-Galactosidase [Type] => general ) [21] => Array ( [SubjectFull] => medicine.anatomical_structure [Type] => general ) [22] => Array ( [SubjectFull] => Cats [Type] => general ) [23] => Array ( [SubjectFull] => Quality of Life [Type] => general ) [24] => Array ( [SubjectFull] => Histopathology [Type] => general ) [25] => Array ( [SubjectFull] => Neurology (clinical) [Type] => general ) [26] => Array ( [SubjectFull] => Sciatic nerve [Type] => general ) [27] => Array ( [SubjectFull] => business [Type] => general ) [28] => Array ( [SubjectFull] => Biomarkers [Type] => general ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis [Type] => main ) ) ) [BibRelationships] => Array ( [HasContributorRelationships] => Array ( [0] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Kayly Nielsen ) ) ) [1] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Thomas N. Seyfried ) ) ) [2] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Cassie N Bebout ) ) ) [3] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Nathan L. Ta ) ) ) [4] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Douglas R. Martin ) ) ) [5] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Kalajan R Lopez Mercado ) ) ) [6] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Devin E Osterhoudt ) ) ) [7] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Stacy Maitland ) ) ) [8] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Ana Rita Batista ) ) ) [9] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Amanda L. Gross ) ) ) [10] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Heather L. Gray-Edwards ) ) ) [11] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Brandon L. Brunson ) ) ) [12] => Array ( [PersonEntity] => Array ( [Name] => Array ( [NameFull] => Miguel Sena-Esteves ) ) ) ) [IsPartOfRelationships] => Array ( [0] => Array ( [BibEntity] => Array ( [Dates] => Array ( [0] => Array ( [D] => 21 [M] => 04 [Type] => published [Y] => 2020 ) ) [Identifiers] => Array ( [0] => Array ( [Type] => issn-print [Value] => 14602156 ) [1] => Array ( [Type] => issn-locals [Value] => edsair ) [2] => Array ( [Type] => issn-locals [Value] => edsairFT ) ) [Numbering] => Array ( [0] => Array ( [Type] => volume [Value] => 145 ) [1] => Array ( [Type] => issue [Value] => 2 ) ) [Titles] => Array ( [0] => Array ( [TitleFull] => Brain : a journal of neurology [Type] => main ) ) ) ) ) ) )
IllustrationInfo