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The recent description of a cohort with both adults and children harboring biallelic pathogenic variants of CUBN changed the paradigm of the management of isolated proteinuria. Indeed, the detection of proteinuria in a patient, regardless of age, often leads to an exhaustive check-up including kidney biopsy but also the prescription of renin-angiotensin system (RAS) blockers to slow the progression of kidney disease. Patients with CUBN variants have nondetrimental proteinuria and are non-responsive to RAS blockers. We herein describe 2 siblings treated for isolated proteinuria for several years, eventually diagnosed with CUBN biallelic pathogenic variants (c.703 C > T and c.10363-3A > G). We review the physio-pathological mechanisms of this newly discovered disease and discuss implications for clinical management. LESS      Full article

Hereditary and autoimmune pancreatitis are two rare forms of inflammatory pancreatic disorders. Both share similarities with acute, acute recurrent, and chronic pancreatitis. Regarding their pathogenesis, the premature activation of the digestive protease trypsinogen and the infiltration of inflammatory cells such as polymorphonuclear leukocytes and macrophages into the pancreas are highly relevant and can reciprocally amplify inflammation. Neutrophil serine proteases are the main components of neutrophil granulocytes and have different pro-inflammatory effects in many diseases. However, their role in pancreatitis is still limited. This section focuses on known findings regarding the role of this group of enzymes in hereditary and autoimmune pancreatitis. LESS      Full article

Drug repurposing represents a real opportunity to address unmet needs and improve the lives of rare disease patients. It is often presented as a faster, safer and cheaper path for bringing drugs into new indications. However, several economic, regulatory and scientific barriers can impede the successful repurposing of drugs for rare diseases. The International Rare Diseases Research Consortium (IRDiRC) set up the Task Force on Sustainable Models in Drug Repurposing with the objective of identifying key factors for achieving sustainable repurposing approaches in rare diseases.In order to help inform expert opinion, the Task Force investigated six cases of medicinal products repurposed into new rare indications and four cases of ongoing development programs. A questionnaire addressing the major steps of the repurposing approach was developed by the Task Force and sent to contact points of the organizations. In addition, interviews were conducted with the relevant organization representatives to conduct a deeper dive into the sustainability of the repurposing approach for each of the selected cases.Based on the collective experience of the members of the Task Force and the output from the questionnaires/interviews, we have identified ten key factors that should be considered by those embarking on repurposing projects. These factors include the identification of unmet patient needs and partnership with patients, collection of evidence concerning disease prevalence, patient numbers, drug pharmacology and disease etiology, drug industrial property status, off-label or compounding use, data from past clinical studies and needs for extended non-clinical and clinical studies. The development of a collaborative funding framework and early discussion with regulators and payers are additional factors to implement early in the development of sustainable drug repurposing projects. LESS      Full article

Aminoacyl-tRNA synthetases are essential, non-redundant enzymes that catalyze the charging of tRNAs with their cognate amino acids. This reaction is a prerequisite for protein translation in all cells. Mutations in human aminoacyl-tRNA synthetases are often associated with defects of the peripheral and central nervous system and are the underlying cause of many rare diseases including neuropathies and leukodystrophies. A comprehensive understanding of aminoacyl-tRNA synthetase expression domains is key to understanding these disorders and developing novel targeted treatment strategies. Here, we describe histological and biochemical methods to analyze the expression pattern of the aspartyl-tRNA synthetase AspRS in human post-mortem brain tissue. The same methods can readily be applied to other members of the aminoacyl-tRNA synthetase superfamily or, more generally, to other cytosolic proteins in the human brain. LESS      Full article

There are different approaches to drug repurposing (DR) depending on the status of the repurposable drug/molecule (approved, investigational, withdrawn, shelved), the context, and the stakeholders involved. The purpose of this perspective paper is to highlight the complexity of academia-industry collaborations in DR for rare diseases and go beyond stereotypes to consider realistic and mutually reinforcing cooperation among various stakeholders, including not only academia and industry but also regulators, legal experts, and payers, leading to benefits for patients with unmet medical needs. Key questions are addressed through the presentation of select DR case studies. Some ongoing and promising European and international initiatives are introduced and some recommendations are proposed. LESS      Full article

The identification and characterization of the four active neutrophil serine proteases (NSPs) have provided a better understanding of their roles in various physiological and pathological processes. The availability of appropriate tools such as substrates, inhibitors, and activity-based probes (ABPs) for studying their activity and functions in cells has become increasingly important. In this paper, the authors provide a comprehensive overview of the current knowledge on the tools available for studying NSPs. The substrates, inhibitors, and ABPs developed to date are described, including their strengths and limitations. The authors also discuss the potential implications of these tools for future research on NSPs, including their potential use in the development of new therapeutics for various diseases. Overall, this paper highlights the importance of understanding the activity and functions of NSPs and provides valuable information on the tools available for studying these proteases. LESS      Full article