Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids.

The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide-protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin's half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.

Parenting school-aged children after the death of a child: A qualitative study on victims' families of the Sewol ferry disaster in South Korea.

This study aims to identify parenting experiences after the death of a child. Using interpretive phenomenological analysis, we mapped the experiences of 16 parents with school-aged surviving children after the death of their sibling to the 2014 Sewol ferry disaster in South Korea. Interviews illuminate five master themes of parenting surviving children following a child's death: (a) parental anxiety, (b) conflicts and obstacles in the parent-child relationship, (c) changes in parenting style, (d) striving to support children's grief, and (e) seeking outside help for parenting. Implications for supporting grieving parents and their children are discussed in light of the findings.

Parental Perceptions of Surviving Sibling Grief Responses to an Adolescent's Violent and Sudden Death by the Sewol Ferry Disaster in South Korea.

The aim of this study was to provide empirical descriptions of responses to the death of a sibling to the sinking of the Sewol ferry in South Korea. 16 bereaved parents are interviewed regarding their surviving children's grief responses at approximately 2 years after the death. The surviving siblings described by the bereaved parents are 14 in total, including 8 teens in their 10s and 4 young adults in their 20s. Interviews were transcribed verbatim and analyzed using a qualitative content analysis method. The following themes emerged: (a) negative behavioral changes, (b) expressions of grief, (c) change in relationship with parents, (d) school adjustment problems, and (e) social changes. Unique aspects of the grief responses among the surviving siblings in this study are noted. Discussions and implications are provided based on the results.

Life Experience of Bereaved Parents After the 2014 Sewol Ferry Disaster in South Korea.

The aim of this study was to identify the outcomes of parental bereavement and the changes in life experience that follow the traumatic death of a teenage child. The results of the study are aimed to assist counselors and educators who work with themes of grief and loss. From 17 in-depth interviews from parents bereaved by the Sewol ferry disaster of 2014 in South Korea, three main categories were found to capture the reality for parents after the sudden and traumatic death of a teenage child: (a) personal changes, (b) changes in close relationships, and (c) changes in social life. Recommendations for future research and potential implications were discussed.

Manufacturing innovation to drive down cell therapy costs.

Chimeric antigen receptor T cells (CAR-T) have demonstrated their potential to revolutionize cancer treatment. However, manufacturing remains a challenge. Multiple manufacturing innovations [e.g., vector and gene engineering, process improvements, hardware innovation, digital innovation, and point-of-care (POC) manufacturing] have the potential to help realize the full potential of CAR-T therapies.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

Intrathecal delivery and its applications in leptomeningeal disease.

Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents-cellular, protein, nucleic acid, and nanoparticle-based small molecules-that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.

An ingestible self-orienting system for oral delivery of macromolecules.

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise's ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator's safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration.