Safety and Efficacy of OXB-202, a Genetically Engineered Tissue Therapy for the Prevention of Rejection in High-Risk Corneal Transplant Patients.

Due to both the avascularity of the cornea and the relatively immune-privileged status of the eye, corneal transplantation is one of the most successful clinical transplant procedures. However, in high-risk patients, which account for >20% of the 180,000 transplants carried out worldwide each year, the rejection rate is high due to vascularization of the recipient cornea. The main reason for graft failure is irreversible immunological rejection, and it is therefore unsurprising that neovascularization (NV; both pre and post grafting) is a significant risk factor for subsequent graft failure. NV is thus an attractive target to prevent corneal graft rejection. OXB-202 (previously known as EncorStat®) is a donor cornea modified prior to transplant by ex vivo genetic modification with genes encoding secretable forms of the angiostatic human proteins, endostatin and angiostatin. This is achieved using a lentiviral vector derived from the equine infectious anemia virus called pONYK1EiA, which subsequently prevents rejection by suppressing NV. Previously, it has been shown that rabbit donor corneas treated with pONYK1EiA substantially suppress corneal NV, opacity, and subsequent rejection in an aggressive rabbit model of cornea graft rejection. Here, efficacy data are presented in a second rabbit model, which more closely mirrors the clinical setting for high-risk corneal transplant patients, and safety data from a 3-month good laboratory practice toxicology and biodistribution study of pONYK1EiA-modified rabbit corneas in a rabbit corneal transplant model. It is shown that pONYK1EiA-modified rabbit corneas (OXB-202) significantly reduce corneal NV and the rate of corneal rejection in a dose-dependent fashion, and are tolerated with no adverse toxicological findings or significant biodistribution up to 13 weeks post surgery in these rabbit studies. In conclusion, angiogenesis is a valid target to prevent corneal graft rejection in a high-risk setting, and transplanted genetically modified corneas are safe and well-tolerated in an animal model. These data support the evaluation of OXB-202 in a first-in-human trial.

Development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors.

It is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (RCL) in lentiviral vector products prior to use in clinical trials. Immune Design previously described an HIV-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (VP02). VP02 is enveloped with E1001, a modified Sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) expressed on dendritic cells in vivo. Vector enveloped with E1001 does not transduce T-cell lines used in standard HIV-1-based RCL assays, making current RCL testing formats unsuitable for testing VP02. We therefore developed a novel assay to test for RCL in clinical lots of VP02. This assay, which utilizes a murine leukemia positive control virus and a 293F cell line expressing the E1001 receptor DC-SIGN, meets a series of evaluation criteria defined in collaboration with US regulatory authorities and demonstrates the ability of the assay format to amplify and detect a hypothetical RCL derived from VP02 vector components. This assay was qualified and used to test six independent GMP production lots of VP02, in which no RCL was detected. We propose that the evaluation criteria used to rationally design this novel method should be considered when developing an RCL assay for any lentiviral vector.

Decreasing the cutoff for elevated blood lead (EBL) can decrease the screening sensitivity for EBL.

Change in the definition of elevated blood lead (EBL) from greater than or equal to 10 µg/dL (cutoff A) to greater than or equal to 5 µg/dL (cutoff B) was recently endorsed in the United States. A potential effect of this change is to decrease the screening sensitivity for EBL detection. We demonstrate this effect by simulated sampling of an example patient distribution for lead. Using lead-dependent assay imprecision, simulated sampling of the patient distribution tracked individual misclassifications relative to the EBL cutoff. Decreasing the EBL cutoff from A to B reduced screening sensitivity for EBL detection in this population to less than 90%, a decrease of 4%. The result was due to the fact that, for B, a greater fraction of the EBL population was near the EBL cutoff and therefore subject to misclassification due to assay imprecision. The effect of the decreased EBL cutoff to reduce EBL screening sensitivity is likely to apply to EBL screening programs generally.

Intimate partner violence and patient screening across medical specialties.

OBJECTIVES: The aims of this study were to compare rates of intimate partner violence (IPV) across different medical specialties and health care sites in one metropolitan area, describe demographic characteristics of women with abusive partners, characterize health care provider assessment of IPV, and describe patient characteristics associated with health care assessment for partner violence. METHODS: Women (N = 2,465) completed written surveys about partner violence and health care screening for violence in the waiting rooms of five types of health care settings (obstetrician/gynecologist office, emergency department, primary care office, pediatrics, and addiction recovery) across eight different hospitals in the greater Boston area. RESULTS: The overall survey response rate was 62%. The 12-month prevalence rate of IPV was 14%, with 37% disclosing lifetime prevalence. The highest rates of recent IPV were disclosed in the hospital-based addiction recovery unit (36%) and in emergency departments (17%). Adjusted demographic risk characteristics for IPV included age (younger than 24 years), low income, and unemployment. Health care providers were more likely to discuss IPV with low-income women than with middle- or high-income women but were no more likely to assess violence within the youngest age group. Among women who disclosed abuse to their health care provider, 50% reported receiving direct interventions or services as a result. CONCLUSIONS: Using the same instrument and protocol, different rates of IPV and detection of IPV were found across medical departments, with the highest rates in emergency departments and an addiction recovery program. It is especially important for assessment of IPV to include young women who present to medical departments.

Adverse health behaviors and the detection of partner violence by clinicians.

BACKGROUND: Intimate partner violence (IPV) is a major public health problem in the United States, and victims are commonly encountered in medical settings. Many barriers exist to clinician-initiated screening for IPV. However, smoking and problem drinking are conditions that clinicians commonly screen for and both have been strongly associated with IPV in prior studies. By estimating the predicted probability of 12-month and lifetime IPV for a given patient based on whether she presents with these conditions, our study gives clinicians information that can help them identify patients at risk for IPV. METHODS: A cross-sectional written patient survey was administered to 2386 female patients at 8 different health care settings in the Greater Boston (Mass) metropolitan area. The probabilities of 12-month and lifetime IPV were estimated based on the women's self-report of smoking and drinking behaviors. RESULTS: A woman who neither smoked nor engaged in problem drinking had a 10% probability of IPV in the preceding 12 months and a 39% chance of IPV in her lifetime. Smoking increased the probability to 14% and 49%, respectively. Problem drinking resulted in a doubling of the predicted probability of 12-month IPV to 21%, with a lifetime probability of 43%. When both conditions were present, the effects were additive, with a woman having a 27% probability of experiencing IPV in the preceding 12 months and 54% chance of IPV in her lifetime. CONCLUSIONS: The presence of smoking or problem drinking should raise clinicians' suspicion for IPV. This paradigm should not replace direct questioning about IPV but may aid in the detection of abuse in patient populations.