Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.

Studies have demonstrated that environmental, host genetic, and socioeconomic factors influence the breast cancer prevalence landscape with a far-reaching influence on racial disparity to subtypes of breast cancer. To understand whether breast tissue harbors race-specific microbiota, we performed 16S rRNA gene-based sequencing of retrospective tumor and matched normal tissue adjacent to tumor (NAT) samples collected from Black non-Hispanic (BNH) and White non-Hispanic (WNH) women. Analysis of Triple Negative Breast cancer (TNBC) and Triple Positive Breast Cancer (TPBC) tissues for microbiota composition revealed significant differences in relative abundance of specific taxa at both phylum and genus levels between WNH and BNH women cohorts. Our main findings are that microbial diversity as measured by Shannon index was significantly lower in BNH TNBC tumor tissue as compared to matched NAT zone. In contrast, the WNH cohort had an inverse pattern for the Shannon index, when TNBC tumor tissue was compared to the matched NAT. Unweighted Principle Coordinates Analysis (PCoA) revealed a distinct clustering of tumor and NAT microbiota in both BNH and WNH cohorts.

Objective Brainstem gliomas are common in children and have the worst prognosis of any brain tumor in children. On the other hand, brainstem gliomas are rare in adult, and clinical studies have suggested different biological behavior between young and adult. The present study was designed to develop an orthotropic C6 brainstem glioma model in young and adult rats, and to investigate the tumor biological behavior in the two age groups. Methods C6 glioma cells were stereotactically implanted into the pons of young or adult male rats. Neurological presentation and survival time were recorded. Tumor proliferation and apoptosis in brainstem gliomas of young and adult rats were determined by immunohistochemical staining of Ki-67 and TUNEL assay, respectively. Results Striking difference were found between young and adult brainstem glioma in the onset of neurological signs, duration of symptoms, survival time, tumor growth pattern, as well as tumor proliferation and apoptosis. Relatively focal tumors were observed in adult rats harboring brainstem glioma, while diffusive tumors were found in young rats. Furthermore, brainstem gliomas in adult rats were less proliferative and had more apoptosis than those in young rats. Conclusion The present study demonstrated that C6 brainstem glioma model in young and adult rats closely imitates human brainstem glioma in neurological findings and histopathology. Our findings suggest that the different growth pattern and invasiveness of brainstem glioma between children and adult could be due to the different host cellular environments between the two age groups, hence, warrant further investigation of the different host-response between childhood and adult brainstem glioma in human.

Background The COVID-19 pandemic forced the cancellation of conventional in-person academic conferences due to the risk of virus transmission and limited ability to travel. Both the American Pediatric Surgical Association (APSA) and International Pediatric Endosurgery Group (IPEG) converted to a virtual format for their 2020 annual meetings. The purpose of this article is to review the successful implementation of the APSA and IPEG virtual meetings and reflect upon lessons learned for future virtual conferences. Methods Logistics, structure, and attendance statistics were reviewed. Informal interviews were conducted with key stakeholders and the number of presenters and participants were analyzed. Finally, post-meeting attendee surveys were conducted to elicit feedback after both virtual meetings. Results The meetings were organized in different ways, with APSA spreading a mix of scientific and clinical educational content over several months and IPEG keeping the meeting compressed, similar to previous in-person versions. Both meetings were free and therefore attracted a high proportion of participants (720 for APSA and 834 for IPEG). The meetings were felt to be educationally appropriate by most, although timing and lack of Continuing Medical Education (CME) opportunities were detractors. Most attendees said they would be willing to pay fees similar to in-person amounts. IPEG compressed presentations into four 2-hour sessions spread over 4 weeks, but also made material available on-line through a proprietary application. There was a broad range of international attendees. IPEG attracted a larger percentage of non-members than did APSA (3:1 nonmember to member ratio). Both societies reported net losses, largely due to lost registration revenue and non-refundable costs from having to switch from an in-person meeting. Conclusions The main advantage of the virtual meeting was increased participation while disadvantages included the lack of networking. The key lessons learned from the meetings include methods to increase interactivity, adjustments of technical logistics, and creation of enduring material. In the future, hybrid conferences will likely become more prevalent with advantages of both platforms. Level-of-Evidence Level V - Expert Opinion