Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice.

Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients.

Prevalence of Intimate Partner Violence, Substance Use Disorders and Depression among Incarcerated Women in Lima, Perú.

BACKGROUND: Globally, there is evidence supporting the co-occurrence of intimate partner violence (IPV), substance use disorders (SUD) and mental health disorders among women in prisons, however, there is limited research investigating these domains in the Andean region where rates of female incarceration have increased. The study objective was to explore the prevalence of IPV, SUD and depression among incarcerated women in a Peruvian prison and explore associations among these variables and related correlates. METHODS: 249 incarcerated women responded to a questionnaire about IPV, substance use, depression, and sexual behavior, and were screened for HIV/sexually transmitted diseases (STDs). Univariate analysis and logistic regression were used to estimate relative risk and the influence of substance use and depression on IPV rates. RESULTS: Twelve months prior to incarceration, of the women with sexual partners pre-incarceration (n = 212), 69.3% experienced threats of violence, 61.4% experienced ≥1 acts of physical violence, and 28.3% reported ≥1 act of sexual aggression. Pre-incarceration, 68.1% of drug-using women had a SUD, and 61.7% of those who consumed alcohol reported hazardous/harmful drinking. There were 20 (8.0%) HIV/STD cases; and 67.5% of the women reported depressive symptoms. Compared to women with no experiences of physical violence, a greater proportion of women who experienced least l violent act had depressive symptoms and engaged in sex work pre-incarceration. Depression was associated with physical violence (adjusted relative risk = 1.35, 95% confidence interval: 1.14-1.58). RECOMMENDATIONS: The findings provide evidence of a syndemic of IPV, substance abuse and depression among incarcerated women in a Peruvian prison. To help guide policy makers, further research is needed to determine if this is indicative of trends for other at-risk women in the region, and viable options to treat these women during incarceration to prevent recidivism and other long-term negative sequalae.

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates.

Adeno-associated virus (AAV)-based liver gene therapy has been shown to be clinically successful. However, the presence of circulating neutralizing antibodies (NABs) against AAV vector capsids remains a major challenge as it may prevent successful transduction of the target cells. Therefore, there is a need to develop strategies that would enable AAV-mediated gene delivery to patients with preexisting anti-AAV NABs. In the current study, the feasibility of using an immunoadsorption (IA) procedure for repeated, liver-targeted gene delivery in nonhuman primates was explored. The animals were administered IV with recombinant AAV5 (rAAV5) carrying the reporter gene human secreted embryonic alkaline phosphatase (hSEAP). Seven weeks after the first rAAV treatment, all of the animals were readministered with rAAV5 carrying the therapeutic hemophilia B gene human factor IX (hFIX). Half of the animals administered with rAAV5-hSEAP underwent IA prior to the second rAAV5 exposure. The transduction efficacies of rAAV5-hSEAP and rAAV5-hFIX were assessed by measuring the levels of hSEAP and hFIX proteins. Although no hFIX was detected after rAAV5-hFIX readministration without prior IA, all animals submitted to IA showed therapeutic levels of hFIX expression, and a threshold of anti-AAV5 NAB levels compatible with successful readministration was demonstrated. In summary, our data demonstrate that the use of a clinically applicable IA procedure enables successful readministration of an rAAV5-based gene transfer in a clinically relevant animal model. Finally, the analysis of anti-AAV NAB levels in human subjects submitted to IA confirmed the safety and efficacy of the procedure to reduce anti-AAV NABs. Furthermore, clinical translation was assessed using an immunoglobulin G assay as surrogate.