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Key Points Etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity in severe/moderately severe hemophilia B over 6 months. Etranacogene dezaparvovec eliminated bleeding and need for FIX replacement in patients with preexisting anti-AAV5 neutralizing antibodies.

As gene transfer with adeno-associated virus (AAV) vectors is starting to enter clinical practice, this review examines the impact of vector capsid choice in liver-directed gene transfer for hemophilia. Given that there are multiple clinical trials completed and ongoing in this field, it is important to review the clinical evidence, particularly as a range of AAV-vector serotypes including AAV2, AAV5, AAV8, and AAV10 have been tested. Although there have been a number of successful trials, the development of two investigational AAV vectors for hemophilia B has been discontinued because they did not meet efficacy and/or safety expectations. Whether this difference between success and failure of gene transfer approaches reflects capsid choice, vector design, manufacturing system, or other variables is a question of great interest. Here, we examine the body of evidence across trials to determine the possible influences of serotype choice on key clinical outcomes such as safety, vector clearance, treatment eligibility, occurrence of transaminase elevations, activation of capsid-directed cytotoxic T cell responses, and clinical efficacy. In summary, gene transfer requires a balance between achieving sufficient transgene expression and minimizing destructive immune responses, which may be affected by AAV-vector serotype choice.

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Benzodiazepines are prescribed widely but their utility is limited by unwanted side effects, including abuse potential. The mechanisms underlying the abuse-related effects of benzodiazepines are not well understood, although a1 subunit-containing GABA A receptors have been proposed to have a critical role. Here, we examine the reinforcing effects of several compounds that vary with respect to intrinsic efficacy at a2, a3, and a5 subunit-containing GABA A receptors but lack efficacy at a1 subunit-containing GABA A receptors ('a1-sparing compounds'): MRK-623 (functional selectivity for a2/a3 subunit-containing receptors), TPA023B (functional selectivity for a2/a3/a5 subunit-containing receptors), and TP003 (functional selectivity for a3 subunit-containing receptors). The reinforcing effects of the a1-sparing compounds were compared with those of the non-selective benzodiazepine receptor partial agonist MRK-696, and non-selective benzodiazepine receptor full agonists, midazolam and lorazepam, in rhesus monkeys trained to self-administer midazolam or cocaine, under a progressive-ratio schedule of intravenous (i.v.) drug injection. The a1-sparing compounds were self-administered significantly above vehicle levels in monkeys maintained under a midazolam baseline, but not under a cocaine baseline over the dose ranges tested. Importantly, TP003 had significant reinforcing effects, albeit at lower levels of self-administration than non-selective benzodiazepine receptor agonists. Together, these results suggest that a1 subunit-containing GABA A receptors may have a role in the reinforcing effects of benzodiazepine-type compounds in monkeys with a history of stimulant self-administration, whereas a3 subunit-containing GABA A receptors may be important mediators of the reinforcing effects of benzodiazepine-type compounds in animals with a history of sedative-anxiolytic/benzodiazepine self-administration.

Introduction People with inherited and long‐term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox). Aim To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population. Methods We conducted a discrete choice experiment including duration to capture valuations of health states based on patient‐reported preferences. Participants indicated their preferences for hypothetical health states using the EQ‐5D‐5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional‐logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ‐5D‐5L health states. Results After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ‐5D‐5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity. Conclusion Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.

A consistent observation in drug abuse research is that males and females show differences in their response to drugs of abuse. In order to understand the neurobiology underlying cocaine abuse and effective treatments, it is important to consider the role of sex differences. Sex hormones have been investigated in both behavioral and molecular studies, but further evidence addressing drug abuse and dependence in both sexes would expand our knowledge of sex-differences in response to drugs of abuse. Neuroimaging is a powerful tool that can offer insight into the biological bases of these differences and meet the challenges of directly examining drug-induced changes in brain function. As such, neuroimaging has drawn much interest in recent years. Specifically, positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) technology have emerged as effective non-invasive approaches for human and animal models. Studies have revealed sex-specific changes in patterns of brain activity in response to acute cocaine injection and following prolonged cocaine use. SPECT and PET studies have demonstrated changes in the dopamine transporter but are less clear on other components of the dopaminergic system. This review highlights contributions of neuroimaging toward understanding the role of sex differences in the drug abuse field, specifically regarding cocaine, and identifies relevant questions that neuroimaging can effectively address.