Cancers doi: 10.20517/rdodj.2025.35

Authors: Martin K. Childers,Hui-Chong Lau,Hichem Tasfaout

Gene therapies for muscular dystrophies are limited by the large size of disease-associated genes, which exceed the packaging capacity of standard adeno-associated virus vectors. In a recent Science article, Lindley et al. introduced “StitchR”, a ribozyme-activated RNA trans-ligation platform designed to reconstitute full-length transcripts inside cells, thereby enabling expression of large therapeutic proteins. This commentary evaluates the StitchR platform in the context of existing dual-vector strategies, particularly split-intein systems that have advanced to human clinical trials. We review the mechanistic distinctions, comparative efficiency, and translational readiness of RNA versus protein-level reconstitution, and highlight key unknowns related to immunogenicity, efficiency, and fidelity. While StitchR represents a conceptually elegant and potentially transformative approach, its therapeutic relevance will depend on further validation in additional preclinical studies, regulatory engagement, and head-to-head comparisons with clinically advanced platforms.

Cancers doi: 10.20517/rdodj.2025.58

Authors: Daniel Scherman

Walking ability in Duchenne muscular dystrophy (DMD) deteriorates progressively until complete loss of function. Interventions aimed at maintaining ambulatory ability rely on accurate clinical-based scores and evaluations of walking. The commentary concerns a study that provides a comprehensive look at how contractures, muscle weakness, and gait deviations intertwine to shape mobility in boys with DMD. The described eight-year longitudinal work offers a significant contribution to the understanding of longitudinal gait changes in DMD and the clinical value of such longitudinal data. The findings confirm that gait spatiotemporal parameters, particularly speed, stride length, and cadence, serve as sensitive markers of disease progression, closely linked to specific biomechanical impairments. The study strongly suggests that the integration of quantitative gait metrics into both clinical and research frameworks will be essential for optimizing patient monitoring and evaluating emerging therapeutics.

Cancers doi: 10.20517/rdodj.2025.66

Authors: Bhavya S. Doshi,Julie M. Crudele,Mary Beth Callan

Hemophilia A (HA) and B (HB) are monogenic X-linked disorders caused by plasma coagulant factor VIII (FVIII) and IX (FIX) deficiency, respectively, and occur naturally in a variety of dog breeds. While several animal models of hemophilia exist, the canine model closely mimics the genotypic, phenotypic, and immunologic characteristics of the disorder in humans. Consequently, decades of research were conducted in the canine model of hemophilia, ultimately leading to licensed liver-directed adeno-associated viral (AAV) vector-mediated gene therapy for HA and HB in humans. The studies from both research colony and companion hemophilic dogs with AAV liver-directed gene therapy support the safety and efficacy of this platform in canines. Here, we provide practical considerations with respect to the administration and monitoring of liver-directed AAV gene therapy for hemophilia in veterinary clinical practice and review the data on efficacy and safety of AAV gene therapy in canine hemophilia.

Cancers doi: 10.20517/rdodj.2025.52

Authors: Hannah Kim,Julia Polen,Gurcharanjeet Kaur

Neurofibromatosis type 1-associated plexiform neurofibromas cause significant morbidity and carry a risk of malignant transformation. Early targeted agents failed to demonstrate efficacy, safety, or durable responses until the discovery of mitogen-activated protein kinase kinase (MEK 1/2) inhibitors. Selumetinib and mirdametinib are approved medical therapies that can potentially reduce tumor volume and symptoms, improve patient-reported outcomes, and have manageable toxicities. An indirect comparison between selumetinib and mirdametinib suggests differences in efficacy and safety, but direct confirmatory head-to-head trials are needed. Active clinical trials in the pipeline are exploring other targets in the MEK pathway, along with combination therapies. Key priorities include the impact of malignant peripheral nerve sheath tumor risk, defining long-term safety, durability off therapy, predictors of response and resistance, and implementation of multidisciplinary care.

Cancers doi: 10.20517/rdodj.2025.45

Authors: Yurie Satoh-Kanda,Shingo Nakayamada,Yoshiya Tanaka

It is well known that the failure of multiple past clinical trials in systemic lupus erythematosus (SLE) is partly due to the clinical and immunological heterogeneity of the disease. Appropriate trial designs, endpoints, and patient populations are required to assess the efficacy of SLE treatments. At the same time, interdisciplinary research is gradually revealing multiple targets that contribute to the pathophysiology of SLE. Currently, molecular-targeted therapies tailored to the disease are being developed as treatment strategies that do not rely on glucocorticoids. With the introduction of new treatments and technologies, clinical trials for SLE have significantly accelerated over the past decade. More than 300 interventional studies on SLE and lupus nephritis, both ongoing and planned, are underway. Various trials targeting different pathways are currently being conducted and SLE treatment strategies may be on the verge of a turning point in the near future. However, some challenges remain. In this review, we focus on promising agents in phase 2 clinical trials and beyond to highlight the latest perspectives and unresolved issues related to targeted therapies for SLE, as well as to explore future research directions and therapeutic strategies required for the implementation of personalized medicine for this rare disease.

Cancers doi: 10.20517/rdodj.2025.08

Authors: Katie Liao,Hwai Jien Lee,Eric F. Morand

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that is undergoing a revolution in its treatment paradigm. Receptor kinases including Janus (JAK) kinases, Bruton's tyrosine kinase (BTK), and spleen tyrosine kinase (SYK) are essential for signalling of many cytokines and receptors on immune cells. Suppression of these kinases changes the activation state of target cells, leading to inhibition of cytokine actions and effects such as autoantibody secretion. Therefore, therapeutic kinase inhibitors hold potential as treatments for SLE, but their efficacy and safety remain to be determined. Tyrosine kinase 2 and JAK inhibitors such as deucravacitinib and upadacitinib respectively have shown positive results in phase 2 trials, while further research into the JAK inhibitor baricitinib and BTK and SYK inhibitors has been less encouraging. This review summarises the current state of research on the use of kinase inhibitors in SLE.

Cancers doi: 10.20517/rdodj.2025.26

Authors: Colm Bradley

Gaucher Disease (GD) is a rare, non-malignant inherited lysosomal storage disorder with a strong hematological component. Although the disease is non-malignant, patients are at risk of developing future hematological malignancies. Hematologists are the largest specialty diagnosing the condition, but diagnosis is usually incidental, following investigation for unexplained splenomegaly, thrombocytopenia, or anemia. Hematologists must be alert to the possibility of GD when patients present with unexplained moderate-to-severe splenomegaly, thrombocytopenia, chronic anemia, and osteolytic bone disease. The major barriers to diagnosis are that the common presenting features of GD overlap with those of other common hematological conditions. As a result, GD education needs to be shifted from the spectrum of metabolic disorders into mainstream hematology, especially because fast and accurate diagnosis is important for both the individual patient and their wider family.

Cancers doi: 10.20517/rdodj.2025.11

Authors: Donita Lightner

Neurofibromatosis type 2-related schwannomatosis was first described in 1822. Although it is a different entity with a distinct presentation, it was initially confused with neurofibromatosis type 1 by our forefathers and continues to be confused by clinicians and patients today. Historically, physicians recognized that some patients presented earlier and had more severe phenotypes (Wishart versus Gardner). This has been better understood through genetic and molecular studies, which indicate that the differences are likely related to mosaicism rather than germline mutations. Recently, the nomenclature was changed to Neurofibromatosis type 2-related schwannomatosis, which is more appropriate. Diagnostic criteria have also been modified with the addition of genetic testing results. Treatment remains a conundrum. Historically, surgery has been the mainstay; however, it is risky for large tumors. Vascular endothelial growth factor inhibitors, such as bevacizumab, have been helpful in reducing the size of acoustic schwannomas and have been shown to preserve hearing, along with alleviating other symptoms. However, the medication has clear toxicities, and patients frequently become dependent on treatment or even develop tumor resistance. Numerous trials are ongoing to investigate reduced dosing regimens of vascular endothelial growth factor inhibitors and alternative molecular targets to determine whether the natural progression of the disease can be altered. Gene therapy is on the horizon.