Viral Delivery of the Fat-1 Gene to Treat Post-Traumatic Arthritis with Diet-Induced Obesity

Post-traumatic arthritis (PTA) is arthritis that develops following joint injury, including meniscus and ligament tears. Current treatments for PTA range from over-the-counter medication to knee replacement; however, in the presence of obesity, the levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α,) are more elevated than in non-obese individuals. The role of fatty acids, obesity, and PTA has been examined, with omega-3 fatty acids showing promise as an anti-inflammatory after injury due to its ability to suppress IL-1 and TNF-α. Due to the difficulty in switching patients’ diets, an alternative solution to increasing omega-3 levels needs to be developed. The Fat-1 enzyme, an omega-3 desaturase that has the ability to convert omega-6 to omega-3 fatty acids, may be a good target for increasing the omega-3 levels in the body.

In the first study, we examined whether Fat-1 transgenic mice on a high-fat diet would exhibit lower levels of PTA degeneration following the destabilization of the medial meniscus (DMM). Both male and female Fat-1 and wild-type (WT) littermates were put on either a control diet (10% fat) or an omega-6 rich high-fat diet (60% fat) and underwent DMM surgery. Arthritic changes were examined 12 weeks post-surgery. Fat-1 mice on both the control and high-fat diet showed protection from PTA-related degeneration, while WT mice showed severe arthritic changes. These findings suggest that the omega-6/omega-3 ratio plays an important role in reducing PTA following injury, and demonstrates the potential therapeutic benefit of the Fat-1 enzyme in preventing PTA in both normal and obese patients following acute injury.

Following this, we needed to establish a translatable delivery mechanism for getting the Fat-1 enzyme, which is not present in mammalian cells, into patients. In the second study, we examined whether anti-inflammatory gene delivery of the Fat-1 enzyme would prevent PTA following DMM surgery. In vitro testing of both lentivirus (LV) and adeno-associated virus (AAV) was completed to confirm functionality and conformation of the Fat-1 enzyme after transduction. Male WT mice were placed on an omega-6 rich high-fat diet (60% fat) and underwent DMM surgery; either local or systemic AAV injections of the Fat-1 enzyme or Luciferase, a vector control, were given immediately following surgery. 12 weeks post-surgery, arthritic changes were assessed. The systemic administration of the Fat-1 enzyme showed protection from synovial inflammation and osteophyte formation, while administration of Luciferase did not confer protection. These findings suggest the utility of gene therapy to deliver the Fat-1 enzyme, which has potential as a therapeutic for injured obese patients for the prevention of PTA.

Screening for Sexual Trauma, Intimate Partner Violence and Mental Health Symptoms among HIV Positive South African Women

Background: The psychological sequelae of sexual trauma and physical intimate partner violence (IPV) exposure can lead to poor HIV care outcomes, including poor treatment adherence. This study aimed to estimate the prevalence of and factors associated with mental health symptoms and trauma among HIV positive women. Additionally, the study aimed to assess the feasibility and acceptability of screening for trauma and mental health symptoms among HIV positive South African women. Finally, the study aimed to elicit healthcare workers’ perceptions related to sexual trauma and the provision of care and services for HIV positive women with trauma histories.

Methods: The study utilized a mixed-methods approach that included a cross-sectional survey of 70 HIV positive women recruited through referral sampling and key informant interviews with seven healthcare workers (HCWs). A study-screening instrument consisting of 24 items from standard measures was used to screen women for sexual trauma, physical intimate partner violence (IPV), depression and PTSD. Sexual trauma and IPV were assessed across the lifetime, while depression and PTSD were current assessments. Logistic regression models were used to explore the relationship between trauma exposure and mental health symptoms, while controlling for age and education. Interview transcripts were coded and analyzed for emergent themes on HCWs perceptions on sexual trauma and HIV care.

Results: Among participants, 51% had sexual trauma experience and 75% had intimate partner violence (IPV) experience. Among participants, 36% met screening criteria for major depression; among those with traumatic experiences (n=57), 70% met screening criteria for post-traumatic stress disorder (PTSD). Compared to having no sexual trauma or IPV exposure, having both sexual trauma and IPV was significantly associated with higher odds of depression (OR = 8.11; 95% CI 1.48-44.34), while having either IPV or sexual trauma individually was not significantly associated with increased odds of depression. Compared to having either IPV or sexual trauma, having both sexual trauma and IPV was not significantly associated with PTSD. Responses from participants’ feedback on screening process suggest that screening was feasible and acceptable to participants. Some of the health care workers (HCWs) did not perceive dealing with trauma to be part of their duties, but instead viewed social workers or psychologists as the appropriate health cadre to provide care related to trauma and mental health.

Conclusions: High levels of sexual trauma, IPV and mental health distress were reported among HIV positive women in this setting. Screening for trauma and mental health symptoms was acceptable to the participants, but several challenges were encountered in implementing screening. Given the potential impact of trauma and mental health on HIV care engagement, interventions to address trauma and its psychological sequelae are needed.