Characteristics of magnetic resonance imaging biomarkers in a natural history study of golden retriever muscular dystrophy

AbstractThe goal of this study was to assess whether magnetic resonance imaging (MRI) biomarkers can quantify disease progression in golden retriever muscular dystrophy (GRMD) via a natural history study. The proximal pelvic limbs of ten GRMD and eight normal dogs were scanned at 3, 6, and 9–12months of age. Several MRI imaging and texture analysis biomarkers were quantified in seven muscles. Almost all MRI biomarkers readily distinguished GRMD from control dogs; however, only selected biomarkers tracked with longitudinal disease progression. The biomarkers that performed best were full-length muscle volume and a texture analysis biomarker, termed heterogeneity index. The biceps femoris, semitendinosus and cranial sartorius muscles showed differential progression in GRMD versus control dogs. MRI features in GRMD dogs showed dynamic progression that was most pronounced over the 3- to 6-month period. Volumetric biomarkers and water map values correlated with histopathological features of necrosis/regeneration at 6-months. In conclusion, selected MRI biomarkers (volume and heterogeneity index) in particular muscles (biceps femoris, semitendinosus, and cranial sartorius) adjusted for age effect allow distinction of differential longitudinal progression in GRMD dogs. These biomarkers may be used as surrogate outcome measures in preclinical GRMD trials

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Characteristics of magnetic resonance imaging biomarkers in a natural history study of golden retriever muscular dystrophy

AbstractThe goal of this study was to assess whether magnetic resonance imaging (MRI) biomarkers can quantify disease progression in golden retriever muscular dystrophy (GRMD) via a natural history study. The proximal pelvic limbs of ten GRMD and eight normal dogs were scanned at 3, 6, and 9–12months of age. Several MRI imaging and texture analysis biomarkers were quantified in seven muscles. Almost all MRI biomarkers readily distinguished GRMD from control dogs; however, only selected biomarkers tracked with longitudinal disease progression. The biomarkers that performed best were full-length muscle volume and a texture analysis biomarker, termed heterogeneity index. The biceps femoris, semitendinosus and cranial sartorius muscles showed differential progression in GRMD versus control dogs. MRI features in GRMD dogs showed dynamic progression that was most pronounced over the 3- to 6-month period. Volumetric biomarkers and water map values correlated with histopathological features of necrosis/regeneration at 6-months. In conclusion, selected MRI biomarkers (volume and heterogeneity index) in particular muscles (biceps femoris, semitendinosus, and cranial sartorius) adjusted for age effect allow distinction of differential longitudinal progression in GRMD dogs. These biomarkers may be used as surrogate outcome measures in preclinical GRMD trials

Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study

Summary Background Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. Methods MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. Findings We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. Interpretation In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Funding Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health