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Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

ABSTRACT: G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in ?-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum ?-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, ?-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain ?-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD-LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy.

SUBMITTER: Walia JS

PROVIDER: S-EPMC4351464 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

Walia Jagdeep S JS Altaleb Naderah N Bello Alexander A Kruck Christa C LaFave Matthew C MC Varshney Gaurav K GK Burgess Shawn M SM Chowdhury Biswajit B Hurlbut David D Hemming Richard R Kobinger Gary P GP Triggs-Raine Barbara B

Molecular therapy : the journal of the American Society of Gene Therapy 20141217 3

G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosami ...[more]

PMID: 25515709

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Project description:ImportanceThe risk of epilepsy after neonatal invasive Group B Streptococcus (iGBS) disease, particularly iGBS sepsis, is poorly understood.ObjectiveTo examine the association between neonatal iGBS (sepsis or meningitis) and long-term risk of epilepsy, stratified by sex, prematurity, and maternal socioeconomic position (SEP).Design, setting, and participantsThis population-based cohort study was conducted in Denmark with an inclusion period from 1997 through 2017 and follow-up until the end of 2018. A general population comparison cohort was randomly sampled and matched up to 10:1 to the exposed cohort. Linkage between Danish national registers were applied for data collection. Participants were infants aged 0 to 89 days. The general population comparison cohort was matched by sex, the child's year and month of birth, and gestational age. SEP was defined by maternal income and education.ExposureHospital-diagnosed iGBS (sepsis or meningitis) during the first 89 days after birth.Outcomes and measuresEpilepsy was defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and/or prescription codes for antiepileptic drugs using Danish medical registry data. Cumulative risk (CR) of epilepsy was calculated by treating death as a competing event. Cox proportional hazards regression was used to estimate hazard ratios with 95% CIs. Effect modification by sex, prematurity, and maternal SEP was assessed on an additive scale.ResultsA total of 1432 children (792 [55.3%] boys; 1126 [78.6%] with gestational age ≥37 weeks) were identified with iGBS disease: 1264 with sepsis and 168 with meningitis. In the comparison cohort, there were 14 211 children (7869 [55.4%] boys; 11 260 [79.2%] with gestational age ≥37 weeks). The overall (0 to 22 years) CR of epilepsy was 3.6% (95% CI, 2.6%-5.0%) in children with iGBS disease and 2.3% (95% CI, 1.9%-2.7%) in the comparison cohort. The overall CR of epilepsy for iGBS meningitis was 15.1% (95% CI, 8.9%-22.8%) and 2.2% (95% CI, 1.4%-3.4%) for iGBS sepsis. The adjusted hazard ratio for epilepsy in children with iGBS disease was 2.04 (95% CI, 1.46-2.85). Being a boy, born premature, or born to a mother belonging to a low SEP group was associated with an increased risk of epilepsy in later childhood.ConclusionIn this population-based cohort study of 1432 neonates, iGBS disease was associated with a higher incidence of epilepsy in later childhood, notably after meningitis. Premature birth, sex, and low maternal SEP modified the association.

Dataset Information

Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

Publications

Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

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