Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy.

Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 1010 vg/eye resulted in transduction of 18%-85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM.

Enterococcus exceedances related to environmental variability at New Jersey ocean beaches.

Microbial pollution at ocean beaches is a global public health problem that can be exacerbated by excessive rainfall, particularly at beaches adjacent to urban areas. Rain is acknowledged as a predictive factor of Enterococcus levels at NJ beaches, but to date no study has explicitly examined the link. Here, five beaches (156 observations) in Monmouth County, NJ, with storm drain outflows present were sampled for Enterococcus and water quality during dry and wet periods. Hypotheses included (1) beaches differ in Enterococcus levels, (2) Enterococcus is present year-round, and (3) Enterococcus exceedances could be modeled based on environmental parameters. Beaches showed significantly different median Enterococcus levels, with site SEA2 (Neptune Blvd. in Deal, NJ) lower than others and site SEA4 (South Bath Ave. in Long Branch, NJ) higher than the other sites. Elevated Enterococcus levels were detected at water temperatures from 6.5 to 22.2 °C. Multiple linear regression models identified rainfall (+), water temperature (+), and water level (-) as related to Enterococcus concentrations levels at these beaches. For the purpose of simulating the efficacy of different monitoring strategies, a hindcast model of Enterococcus abundance based on historic rainfall, water temperature, and water level data was produced. Results indicated that once-per-week sampling detected ~14% (e.g., 1/7) exceedance events, while sampling during summer alone detected ~ 50% of annual exceedance events. Models of Enterococcus exceedance based on readily available environmental time series have the potential to supplement and improve Enterococcus monitoring at NJ beaches.

Long-Term Safety Evaluation of Continuous Intraocular Delivery of Aflibercept by the Intravitreal Gene Therapy Candidate ADVM-022 in Nonhuman Primates.

Purpose: To evaluate the long-term safety of vascular endothelial growth factor (VEGF) suppression with sustained aflibercept expression after a single intravitreal injection (IVI) of ADVM-022, an anti-VEGF gene therapy, in non-human primates (NHPs). Methods: Non-human primates received bilateral IVI of ADVM-022, a gene therapy vector encoding aflibercept, a standard of care for the treatment of VEGF-based retinal disease. Aflibercept levels from ocular fluids and tissues were measured. Ocular inflammation was assessed by slit lamp biomicroscopy and fundoscopy. The integrity of the retinal structure was analyzed by optical coherence tomography and blue light fundus autofluorescence and electroretinography was performed to determine retinal function. Histologic evaluation of the retina was performed at the longest time point measured (2.5 years after injection). Results: Sustained expression of aflibercept was noted out to the last time point evaluated. Mild to moderate inflammatory responses were observed, which trended toward spontaneous resolution without anti-inflammatory treatment. No abnormalities in retinal structure or function were observed, as measured by optical coherence tomography and electroretinography, respectively. RPE integrity was maintained throughout the study; no histologic abnormalities were observed 2.5 years after ADVM-022 IVI. Conclusions: In non-human primates, long-term, sustained aflibercept expression and the resulting continuous VEGF suppression by a single IVI of ADVM-022, appears to be safe, with no measurable adverse effects on normal retinal structure and function evaluated out to 2.5 years. Translational Relevance: Together with the results from previous ADVM-022 preclinical studies, these data support the evaluation of this gene therapy candidate in clinical trials as a potential durable treatment for various VEGF-mediated ophthalmic disorders.

What Can Be Learned From Crowdsourced Population Asparagus Urinary Odor Kinetics?

Asparagus consumption is associated with the production of malodorous urine. Interindividual variability was previously characterized by an American Society for Clinical Pharmacology and Therapeutics crowdsourced study. To further characterize urinary odor kinetics, we conducted a study with consenting participants from Takeda Pharmaceutical International Company. The participants were randomized to consume a specified number of asparagus spears and asked to record urine odor. A kinetic-pharmacodynamic model characterized the data from both the newly conducted Takeda study (N = 42) and the previously analyzed American Society for Clinical Pharmacology and Therapeutics studies (total N = 139). The updated model included the identification of an absorption process with a half-life of 25 minutes. We estimated the elimination half-life of the asparagus effect on malodorous urine to be 7.2 hours, which was 44% longer in our study. We built on previous experience using an improved R-Shiny app for conducting the crowdsourcing experiment, further demonstrating the utility of this population kinetics approach in organizational and educational settings.

Retrospective Analysis of an Ongoing Group-Based Modified Constraint-Induced Movement Therapy Program for Children with Acquired Brain Injury.

AIM: A pretest-posttest retrospective design was used to evaluate the impact of a group-based modified constraint-induced movement therapy (mCIMT) program on upper extremity function and occupational performance. METHODS: 20 children ages 3 to 18 years with hemiplegia following an acquired brain injury participated in a 2-week group mCIMT program. Upper extremity function was measured with the Assisting Hand Assessment (AHA) and subtests from the Quality of Upper Extremity Skills Test (QUEST). Occupational performance and satisfaction were assessed using the Canadian Occupational Performance Measure (COPM). Data were analyzed using a Wilcoxon signed-ranks test. RESULTS: Group-based analysis revealed upper extremity function and occupational performance attained statistically significant improvements from pre- to postintervention on all outcome measures (AHA: Z = -3.63, p = <.001; QUEST Grasps: Z = -3.10, p = .002; QUEST Dissociated Movement: Z = -2.51, p = .012; COPM Performance: Z = -3.64, p = <.001; COPM Satisfaction: Z = -3.64, p = <.001). Across individuals, clinically significant improvements were found in 65% of participants' AHA scores. 80% of COPM Performance scores and 70% of COPM Satisfaction scores demonstrated clinically significant improvements in at least one identified goal. CONCLUSIONS: This study is an initial step in evaluating and providing preliminary evidence supporting the effectiveness of a group-based mCIMT program for children with hemiplegia following an acquired brain injury.

Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer.

PURPOSE: Performance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain. PATIENTS AND METHODS: Individual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade > or = 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy. RESULTS: Compared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade > or = 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients. CONCLUSION: In clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.

Colon cancer in older adults.

Colorectal cancer (CRC) is a common malignancy in the elderly. Randomized trials have demonstrated that adjuvant and palliative chemotherapy for CRC improves survival and quality of life. Unfortunately, there is a lack of evidence-based data about elderly patients to guide decisions regarding therapy. Clinical trials have generally excluded the vulnerable elderly population commonly seen in practice and included the robust elderly, who seem to benefit from chemotherapy as much as younger patients. The existing literature consists of pooled datasets from large studies and a few small dedicated trials on chemotherapy and its toxicity in elderly patients with CRC. We present illustrative data in this article and summarize our recommendations for managing the disease in elderly patients in a variety of clinical circumstances.

Managing older patients with colorectal cancer.

Colorectal cancer (CRC) is predominantly a disease of older persons, and our population is aging. Physicians and their older patients commonly face the dilemma of whether or not to give/receive systemic chemotherapy for CRC. Evidence supports the safety and efficacy of systemic chemotherapy in fit older patients motivated enough to enroll onto clinical trials. Conversely, frail older patients are more likely to suffer adverse outcomes when faced with stressors and may not benefit from chemotherapy. However, the majority of patients are neither fit nor frail, and current evidence is insufficient to either quantify or qualify the benefit of chemotherapy for this intermediate group of patients. Thus, treatment decisions must be individualized based on each older person's physical state (eg, their function and degree of comorbidity) and values. Despite a growing body of data, a great deal of work is still needed to establish optimal strategies to care for patients diagnosed with cancer later in life.