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There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Research on entrepreneurial networking suggests that women may be more likely than men to select cofounders based on their resources (e.g., knowledge, skills, and experience), as a means to counteract investor bias. In contrast, research on gender in networking suggests that women may be more likely than men to select cofounders based on interpersonal attraction (e.g., liking, trustworthiness, and familiarity), because it aligns with their preference for stable and harmonious relationships. In this paper, we reconcile this tension and ask: "How, when, and why do women differ from men in how they choose cofounders?" We propose that women entrepreneurs generally prioritize interpersonal attraction and de-prioritize resources because doing so aligns with their interdependent self-construal, but these relationships are mitigated when legitimacy is low, such that women entrepreneurs decrease their use of interpersonal attraction and increase their focus on resources as a means to bolster legitimacy. We find support for our framework across three studies. Our findings reconcile a key tension in the literature and highlight how interdependent self-construals enable women entrepreneurs to flexibly adjust their networking approach to cofounder selection by prioritizing interpersonal attraction when legitimacy is high and by increasing their use of resource seeking when legitimacy is low. [ABSTRACT FROM AUTHOR]

A library of new dinuclear CeIV complexes of the type [NEt4]2[Ce2X6(TP)(sol)2] (X = Cl, ODipp, OSiMe3; sol = py, THF), where TP represents a family of tetraphenolate ligands that control intermetallic distance, are readily made in good yields. The ligands strongly stabilize the cerium +4 oxidation state and allow the incorporation of alkylammonium cocations in an "ate"complex formulation that enables them to be used as soluble, single-component catalysts for the ring-opening copolymerization (ROCOP) of a variety of anhydrides and epoxides. High turnover frequencies (TOFs) are achieved with high ester linkage selectivity, low dispersities, and rates that are highly tunable by the intermetallic distance enforced by the TP ligand, demonstrating that a closely coupled di-CeIV unit provides excellent rates of ROCOP catalysis and that, more generally, rare-earth complexes deserve further attention as ROCOP initiators.

Disruptions in the gene encoding methyl-CpG binding protein 2 (MECP2) underlie complex neurodevelopmental disorders including Rett Syndrome (RTT), MECP2 duplication disorder, intellectual disabilities, and autism. Significant progress has been made on the molecular and cellular basis of MECP2-related disorders providing a new framework for understanding how altered epigenetic landscape can derail the formation and refinement of neuronal circuits in early postnatal life and proper neurological function. This review will summarize selected major findings from the past years and particularly highlight the integrated and multidisciplinary work done at eight NIH-funded Intellectual and Developmental Disabilities Research Centers (IDDRC) across the US. Finally, we will outline a path forward with identification of reliable biomarkers and outcome measures, longitudinal preclinical and clinical studies, reproducibility of results across centers as a synergistic effort to decode and treat the pathogenesis of the complex MeCP2 disorders.

The article reviews a session from the 2024 Ecological Society of America Annual Meeting focused on engaging students in socioecological systems. Presentations discussed climate change education, diversity in STEM programs, engaging with diverse perspectives in socioecological systems, and using conceptual mapping as an educational tool. The session highlighted the importance of training future ecologists in understanding complex socioecological systems and emphasized the need for more research and practice in this area. The authors also stressed the significance of diversity of perspectives in addressing global socioenvironmental issues. [Extracted from the article]

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader–Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. Methods: We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. Results: With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. Conclusions: RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes. [ABSTRACT FROM AUTHOR]

Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of- function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global Developmental delay, and subsequent intellectual disability, secondary microcephaly, and epilepsy. We preformed preclinical studies evaluating an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50 and describe in vitro studies that demonstrate transduction of patient-derived fibroblasts with AAV2/AP4M1, resulting in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1- KO mice were intrathecally (i.t.) injected with 5 * [10.sup.11], 2.5 * [10.sup.11], or 1.25 * [10.sup.11] vector genome (vg) doses of AAV9/AP4M1 at P7-P10 or P90. Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in WT mice, rats, and nonhuman primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1 * [10.sup.15] vg. Of note, similar degrees of minimal-to-mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future i.t. AAV studies. These preclinical results identify an acceptably safe and efficacious dose of i.t.- administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50., Introduction Hereditary spastic paraplegia 50 (SPG50; OMIM: 612936) is an ultrarare childhood-onset neurological disorder characterized by progressive spastic paraplegia, global Developmental delay, and subsequent intellectual disability, secondary microcephaly, early-onset epilepsy, [...]