New England Journal of Medicine最新文献

Background: Wild-type female Aedes aegypti mosquitoes that mate with male A. aegypti mosquitoes that have been infected with the wAlbB strain of Wolbachia pipientis bacteria produce nonviable offspring owing to cytoplasmic incompatibility. Repeated releases of wolbachia-infected males can potentially suppress wild-type mosquito populations and reduce the risk of dengue virus infection.

Methods: We conducted a trial involving the release of male A. aegypti mosquitoes infected with the wAlbB strain of wolbachia bacteria for the control of dengue in Singapore, a tropical city-state. In this cluster-randomized trial with test-negative controls, we divided 15 geographic population clusters into two groups: 8 clusters received deployments of male wolbachia-infected mosquitoes (intervention clusters) and 7 clusters received no deployments (control clusters). The primary end point was the diagnosis of symptomatic dengue virus infection of any severity caused by any serotype of the virus, as measured by the odds ratio for the distribution of wolbachia exposure among laboratory-confirmed reported dengue cases as compared with test-negative controls.

Results: A total of 393,236 residents lived in the intervention clusters, and 331,192 lived in the control clusters. Adult wild-type A. aegypti populations were suppressed across the intervention clusters. The baseline average abundance of the mosquitoes (number of adult female mosquitoes trapped divided by number of traps) was 0.18 and 0.19 in the intervention and control clusters, respectively; from 3 months after the initiation of the intervention until the end of the 24-month trial period, the average abundance was 0.041 and 0.277, respectively. In the intention-to-treat analysis at 6 months or more, the percentage of residents in the intervention clusters who were dengue-positive was lower than that in the control clusters (354 of 5722 tests [6%] vs. 1519 of 7080 tests [21%]). The protective efficacy of the intervention, calculated as (1 - odds ratio) × 100, ranged from 71 to 72% with 3 to 12 months or more of wolbachia mosquito exposure, as represented by odds ratios of 0.28 to 0.29.

Conclusions: Release of sterile wolbachia-infected male A. aegypti mosquitoes reduced vector populations and the risk of dengue infection in Singapore. (Funded by the Singapore Ministry of Finance and others; ClinicalTrials.gov number, NCT05505682.).

Background: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.

Methods: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.

Results: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.

Conclusions: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).