Lessons from an Experiential Approach to Patient Community Engagement in Rare Disease

Meaningful engagement between biopharmaceutical companies and patient communities has increasingly become an important part of the therapeutic-development process, as such engagement improves the understanding of the multifaceted challenges and unmet needs that communities experience and provides an opportunity to inform the approach to the development of new therapies and services. Presented here are learnings from a community-advisor program designed to engage families of patients with Duchenne muscular dystrophy (DMD) in a manner that enabled caregivers to make valuable contributions to the therapeutic-development process and to the DMD community. Parents of children with DMD, representing the broader DMD community, were identified in partnership with patient-advocacy organizations and invited to participate in a community-advisor meeting with members of Wave Life Sciences. The community-advisor meeting was designed to provide participants with an opportunity to share their personal experiences with DMD, to help to inform the therapeutic-development process, and to identify potential solutions for addressing unmet needs. Three community-advisor meetings were held with a total of 30 parents, representing 36 children with DMD. Key themes that emerged from the advisors' discussion included the importance of the community's emotional and mental support, the inconsistencies in DMD care, the increased challenges and disparities faced by underserved communities, and the need for more comprehensive, holistic approaches to the treatment and management of DMD. The advisors viewed the meetings as an opportunity to share their voices with a biopharmaceutical company, coupled with the advantage of meeting other families living with similar challenges. Most of the advisors stated that this was their first advisor meeting. This community-focused approach empowered participants to voice their needs and perspectives, to brainstorm potential solutions for addressing those needs, and to initiate and foster connections in ways that had a considerable impact on one another and on therapeutic-development programs at Wave Life Sciences.     

Urinary arginine methylation index associated with ambulatory blood pressure abnormalities in children with chronic kidney disease

Arginine (ARG) metabolites are interrelated and are involved in chronic kidney disease (CKD) and cardiovascular disease. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) appears to correlate with cardiovascular outcomes. We investigated the relationship between ARG metabolites, and their combined ratios in urine, and the ABPM profiles of children and adolescents with CKD. This cross-sectional study included 45 children and adolescents (age, 5–18 years) with stage 1 to 4 CKD. Each child underwent office blood pressure (BP) measurements, 24-hour ABPM, and urinary ARG metabolite determinations. Seventy percent of children with CKD had abnormal 24-hour ABPM profiles, including nocturnal hypertension, increased BP load, and nondipping nocturnal BP. The urinary ARG-to-asymmetric dimethylarginine (ADMA) ratio was lower, and the ADMA-to-symmetric dimethylarginine (SDMA) ratio was higher in children with advanced CKD (stages 2–4) than those with stage 1 CKD. CKD patients with BP abnormalities also had reduced urinary ARG and dimethylamine (DMA) levels. The higher urinary (ADMA+SDMA)-to-ARG ratios were correlated to ABPM abnormalities, including increased systolic BP load and non-dipping nocturnal BP. ABPM abnormalities were significantly associated with a high urinary (ADMA+SDMA)-to-ARG ratio, suggesting the possible involvement of methylated ARG in the development of hypertension among children with CKD.     

Combination of a chemopreventive agent and paclitaxel in CD44-targeted hybrid nanoparticles for breast cancer treatment

The CD44 receptor, which is upregulated in many cancer cells, provides a selective cellular surface for targeted drug delivery systems. We developed a hybrid nanocarrier for the CD44-targeted delivery of ibuprofen (IBU) and paclitaxel (PTX). The solid lipid nanoparticles (SLNs) were prepared by a hot-melt oil/water emulsion technique and then coated with hyaluronic acid (HA) by electrostatic interactions. The final SLN were spherical with a hydrodynamic diameter (Z) of 72.16 ± 2.9 nm, polydispersity index (PDI) of 0.276 ± 0.009, and zeta potential (ZP) of 28.20 ± 0.69 mV. Similarly, SLN coated with HA (SLN-HA) exhibited acceptable physical properties (Z 169.3 ± 0.55 nm, PDI 0.285 ± 0.004, and ZP ? 10.5 ± 0.15 mV). Cell viability assays showed that the combination of IBU, a chemopreventive agent, and PTX exerted a synergistic inhibitory effect on the proliferation of cancer cells (CI < 1.0). Additionally, our observations indicated that both SLN and SLN-HA enhanced apoptosis and cellular uptake compared to the cocktail of free drugs. HA indicated its affinity for cancer cells through the improvement of cellular uptake and induction of apoptosis. These results clearly indicated that these nanoparticle systems hold great promise for drug delivery in breast cancer treatment.     

Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

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Renal Transplantation: Relationship between Hospital/Surgeon Volume and Postoperative Severe Sepsis/Graft-Failure. A Nationwide Population-Based Study

Background and objects: We explored the relationship between hospital/surgeon volume and postoperative severe sepsis/graft-failure (including death).Methods: The Taiwan National Health Insurance Research Database claims data for all patients with end-stage renal disease patients who underwent kidney transplantation between January 1, 1999, and December 31, 2007, were reviewed. Surgeons and hospitals were categorized into two groups based on their patient volume. The two primary outcomes were severe sepsis and graft failure (including death). The logistical regressions were done to compute the Odds ratios (OR) of outcomes after adjusting for possible confounding factors. Kaplan-Meier analysis was used to calculate the cumulative survival rates of graft failure after kidney transplantation during follow-up (1999-2008).Results: The risk of developing severe sepsis in a hospital in which surgeons do little renal transplantation was significant (odds ratio [OR]; p = 0.0115): 1.65 times (95% CI: 1.12-2.42) higher than for a hospital in which surgeons do many. The same trend was true for hospitals with a low volume of renal transplantations (OR = 2.39; 95% CI: 1.62-3.52; p < 0.0001). The likelihood of a graft failure (including death) within one year for the low-volume surgeon group was 3.1 times higher than for the high-volume surgeon group (p < 0.0001); the trend was similar for hospital volume. Female patients had a lower risk than did male patients, and patients ≥ 55 years old and those with a higher Charlson comorbidity index score, had a higher risk of severe sepsis.Conclusions: We conclude that the risk of severe sepsis and graft failure (including death) is higher for patients treated in hospitals and by surgeons with a low volume of renal transplantations. Therefore, the health authorities should consider exporting best practices through educational outreach and regulation and then providing transparent information for public best interest.