One of the biggest challenges in adeno-associated virus gene delivery for Duchenne muscular dystrophy (DMD) is that some patients cannot be treated due to pre-existing neutralizing antibodies. As an alternative, nanovesicles derived from diverse human cells have emerged as highly efficient delivery vehicles for genetic materials. This is due to their superior biocompatibility and capability to cross diverse tissue barriers. Notably, the lack of strong host immune response was witnessed in multiple preclinical studies, as well as clinical trials recently completed using human allogeneic nanovesicles. Engineering nanovesicles with tissue-specific ligands on the surface can also enhance tissue selectivity, thus reducing off-target effects. Taken together, these findings raise the possibility that this novel non-viral approach can serve as an attractive alternative to risk-prone viral-mediated gene therapy. This review discusses the recent advances in a non-viral gene therapy approach using cell-derived nanovesicles, and highlights their therapeutic potential in treating neuromuscular diseases, such as DMD, along with current challenges that need to be further addressed.

The complexity of the funding landscape for rare diseases (RD) research is due to many factors. Each type of funder has strategic goals guiding its investments. The International Rare Diseases Research Consortium (IRDiRC) convened RD experts to explore contributing factors and investment principles in RD funding. This report includes the Task Force’s findings. Similar to IRDiRC’s previous work on motivating factors for company investments in RD research, the current Task Force found that return on investment (ROI) was a guiding principle. However, within the broader RD funding landscape, the definition of ROI varied between types of funders. While they shared funding requirements (e.g., scientific quality, health economics), funders employed both major investment and venture-type instruments, demonstrating the ongoing need for flexibility in supporting RD funding. These observations warrant further analysis of the interactions and partnerships among all actors of RD research and the sustainability of RD research funding.

This study investigates the respiratory abnormalities in Dravet Syndrome (DS) through a detailed case report and a narrative literature review. We report the case of a 4-year-old girl, harboring a de novo SCN1A mutation, who exhibited recurrent hypoxemic respiratory failure during febrile infections, not constantly associated with seizures or status epilepticus. In addition, a comprehensive review, including 21 cases, highlights the multifaceted nature of respiratory complications in DS. Notably, severe episodes could occur during common respiratory febrile infections, suggesting an association between DS and increased respiratory risk during febrile illnesses. In fact, the severity and persistence of hypoxemia, even during mechanical ventilation, suggest potential subacute respiratory impairment following seizures and/or infections. The proposed hypothesis of autonomic dysregulation could provide a framework for understanding the intricate relationship between neurological, cardiac, and respiratory functions in DS. This study emphasizes the need for tailored clinical management during febrile illnesses, considering the potential for apnea-related arrhythmias and challenging-to-treat hypoxemia. Further research, including longitudinal studies and advanced physiological monitoring, is crucial for refining our understanding and informing targeted interventions for respiratory abnormalities in DS.

The occurrence of severe adverse events (SAEs) in patients with Duchenne muscular dystrophy (DMD), X-linked myotubular myopathy (XLMTM), and other neuromuscular diseases treated with adeno-associated virus (AAV) constructs has prompted studies to improve the safety and efficacy of gene therapy. Physicians have weighed the medical tenet of “first, do no harm” against the perspective of patients with progressive life-threatening conditions who may accept greater risk. Regarding SAE pathogenesis, discussion has focused on total AAV exposure and patient mutations more likely to induce immunity, while stressing the limitations of animal models in predicting adverse events. Therapeutic strategies for reducing side effects have employed more myotropic AAV serotypes and efficient transgenes. Other recommendations include excluding certain DMD gene mutations associated with SAEs and substituting less immunogenic transgenes such as utrophin (DMD) and myotubularin-related protein (XLMTM). For the sake of preclinical studies, emphasis has been placed on outbred rodents and larger animals that better predict immunity. Here, the absence of side effects in canine DMD and XLMTM models might be explained partly by phenotypic differences between affected humans and dogs. Specifically, dystrophin- and myotubularin-deficient dogs exhibit milder lesions, including less muscle fat deposition and the absence of hepatopathy, respectively, which could lead to reduced immune responses to AAV constructs. To better predict future problems, thought should be given to tracking early subclinical markers of the innate immune response, especially complement activation. Regardless of steps taken to improve the predictive value of animal models for SAEs, some questions will only be answered through human clinical trials after carefully considering the risk-benefit ratio.

Prader-Willi syndrome (PWS) is a multifaceted congenital disorder resulting from the absence of paternally imprinted genes on chromosome 15q11.2-q13.1. Its clinical features vary with age, initially presenting as severe hypotonia and feeding difficulties in infancy, followed by hyperphagia in early childhood, ultimately leading to significant obesity. According to the underlying mechanism, the PWSs are divided into three main types. The deletion type with only one maternal copy accounts for 65%-75% of patients and may be divided into subtypes I to IV. Maternal uniparental disomy (mUPD) has two maternal copies, accounting for 20%-30% of patients, and is divided into the isodisomy subtype and heterodisomy subtype. Imprinting defects account for less than 5% of patients and are divided into epimutation and imprinting center deletions. The genotype-phenotype correlation has recently been investigated. Differences in the frequency and severity of specific features among various genotypes, particularly between deletion and mUPD types, have been reported. Herein, we reviewed the current literature and evidence on the genotype-phenotype correlation in PWS, which may help us to understand the mechanism and reasonable management of PWS.