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1.
Blood ; 143(23): 2373-2385, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38452208

RESUMO

ABSTRACT: Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous; and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e-4 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.


Assuntos
Dependovirus , Fator VIII , Terapia Genética , Vetores Genéticos , Hemofilia A , Fígado , Animais , Cães , Dependovirus/genética , Hemofilia A/genética , Hemofilia A/terapia , Vetores Genéticos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Terapia Genética/métodos , Feminino , Fator VIII/genética , Técnicas de Transferência de Genes , Integração Viral , Transgenes , Modelos Animais de Doenças
2.
Gene Ther ; 29(12): 720-729, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35513551

RESUMO

Lentiviral vectors (LV) are attractive for permanent and effective gene therapy. However, integration into the host genome can cause insertional mutagenesis highlighting the importance of understanding of LV integration. Insertion site (IS) tethering is believed to involve cellular proteins such as PSIP1/LEDGF/p75, which binds to the virus pre-integration complexes (PICs) helping to target the virus genome. Transcription factors (TF) that bind both the vector LTR and host genome are also suspected influential to this. To determine the role of TF in the tethering process, we mapped predicted transcription factor binding sites (pTFBS) near to IS chosen by HIV-1 LV using a narrow 20 bp window in infected human induced pluripotent stem cells (iPSCs) and their hepatocyte-like cell (HLC) derivatives. We then aligned the pTFBS with these sequences found in the LTRs of native and self-inactivated LTRs. We found significant enrichment of these sequences for pTFBS essential to HIV-1 life cycle and virus survival. These same sites also appear in HIV-1 patient IS and in mice infected with HIV-1 based LV. This in silco data analysis suggests pTFBS present in the virus LTR and IS sites selected by HIV-1 LV are important to virus survival and propagation.


Assuntos
Infecções por HIV , HIV-1 , Células-Tronco Pluripotentes Induzidas , Humanos , Camundongos , Animais , Lentivirus/genética , HIV-1/genética , Integração Viral/genética , Fatores de Transcrição/genética , Sítios de Ligação
3.
Recenti Prog Med ; 115(7): 325-327, 2024.
Artigo em Italiano | MEDLINE | ID: mdl-39011913

RESUMO

Recent discoveries have shown that the effects of physical activity on health are not the same in all its domains. In particular, the health effects of physical activity differ not only in terms of modality and intensity, but also based on the context in which it is carried out. Several studies have observed that those who do a lot of physical activity at work tend to have worse health outcomes than those who do less physical activity at work but more exercise in their free time. This phenomenon has been defined as the "physical activity paradox". However, it is worth reporting that differences in health outcomes have been observed for different socioeconomic positions and that more favorable socioeconomic positions tend to have healthier lifestyles.


Assuntos
Exercício Físico , Estilo de Vida , Fatores Socioeconômicos , Humanos , Nível de Saúde , Estilo de Vida Saudável
4.
Mol Ther Methods Clin Dev ; 32(3): 101294, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39104575

RESUMO

Adeno-associated virus (AAV)-based vectors are used clinically for gene transfer and persist as extrachromosomal episomes. A small fraction of vector genomes integrate into the host genome, but the theoretical risk of tumorigenesis depends on vector regulatory features. A mouse model was used to investigate integration profiles of an AAV serotype 5 (AAV5) vector produced using Sf and HEK293 cells that mimic key features of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene therapy for severe hemophilia A. The majority (95%) of vector genome reads were derived from episomes, and mean (± standard deviation) integration frequency was 2.70 ± 1.26 and 1.79 ± 0.86 integrations per 1,000 cells for Sf- and HEK293-produced vector. Longitudinal integration analysis suggested integrations occur primarily within 1 week, at low frequency, and their abundance was stable over time. Integration profiles were polyclonal and randomly distributed. No major differences in integration profiles were observed for either vector production platform, and no integrations were associated with clonal expansion. Integrations were enriched near transcription start sites of genes highly expressed in the liver (p = 1 × 10-4) and less enriched for genes of lower expression. We found no evidence of tumorigenesis or fibrosis caused by the vector integrations.

5.
BMJ Open Sport Exerc Med ; 10(3): e001957, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224205

RESUMO

Objectives: Our study aimed to investigate how physical activity (PA) changes over an 11-year follow-up among adults from different socioeconomic positions (SEP) near retirement age. Moreover, an analysis of different PA types is considered. Methods: We used data from the EPIC-Italy cohort. We evaluated PA using the Cambridge Physical Activity Index (CPAI) and the metabolic equivalent of tasks (MET) per hour of activity for recreational PA and household PA. Educational level was assessed using the Relative Index of Inequality (RII). Occupational classes were classified according to LIFEPATH Consortium knowledge. Logistic regression was used to analyse PA among SEP and changes during follow-up. Analyses were also conducted separately for sex. Results: The higher educated were more prevalent in the higher quartile of recreational PA than the lower educated both at baseline and follow-up (37% vs 28% and 37% vs 27%, respectively). At the baseline, the lower educated had a higher risk of being physically inactive than the higher educated based on recreational PA (overall OR: 1.50, 95% CI 1.40 to 1.60). Manual workers did not show a higher risk of less PA than professionals/managers (overall OR: 1.03, 95% CI 0.91 to 1.16).At follow-up, the lower educated and manual workers showed a higher risk of being physically inactive (lower educated OR: 1.46, 95% CI 1.37 to 1.56; manual worker OR: 1.33, 95% CI 1.18 to 1.50). The analyses of changes in PA showed that those who were less educated or manual workers had a higher risk of worsening their PA during the follow-up period, particularly women in recreational PA and men in CPAI measurement. Conclusion: Individuals who had a disadvantaged SEP showed a higher risk of performing less PA over time.

6.
Addict Behav ; 155: 108037, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38613856

RESUMO

BACKGROUND AND AIMS: Since the COVID-19 outbreak, people's habits changed radically. In fact, to limit the spread of SARS-CoV-2, governments implemented restrictive measures that influenced the lives of individuals. The aim of this systematic review is to analyze the impact of COVID-19 on gambling by examining three different outcomes: frequency, expenditure, and transition among possible types of gambling. METHODS: All studies assessing the impact of restrictive measures implemented to limit the spread of SARS-CoV-2 on gambling were included. For the search, two different databases were used: Pubmed and CINAHL. Moreover, two different populations were analyzed: the general population, and subjects who used to gamble before SARS-CoV-2 pandemic. All qualitative studies, reports not based on peer-review, and papers in which the statistical unit was not the subject but the gambling or wagering operators were excluded. RESULTS: From the search, 408 reports were identified. Of these, 28 were included in the systematic review. From the studies, a strong reduction in the frequency and expenditure of land-based gambling emerged, while the results about online gambling were different among the studies. However, a reduction was observed assessing sports betting, and an increase emerged considering online casino and skill games. Finally, a significant migration from land-based gambling to online platforms was identified. The main reasons for these findings were the physical closures of land-based gambling venues and the more time spent at home, the suspension or cancelation of sporting events on which subjects used to bet, and more mental health issues during this challenging period. CONCLUSIONS: The COVID-19 pandemic greatly affected subjects' habits, including gambling, by reducing land-based gambling and sports betting, and increasing gambling on online platforms. This shift poses significant challenges, requiring a comprehensive approach to monitor and mitigate the negative consequences of this increase in online gambling caused by the pandemic.


Assuntos
COVID-19 , Jogo de Azar , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Jogo de Azar/epidemiologia , Jogo de Azar/psicologia , Pandemias , SARS-CoV-2
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