脊髄性筋萎縮症

The therapeutic application of base editors is limited by their large sizes, which are beyond the packaging capabilities of adeno-associated viral (AAV) vectors. Despite recent progress that has identified many compact CRISPR proteins, the resulting miniature base editors often exhibit reduced activities and limited targeting scope. Here, we introduce a zinc finger protein (ZFP)-enhanced miniature base editor (zmBE), which integrates programmable ZFPs to improve efficiencies and targeting scopes of miniature base editors, including those based on Un1Cas12f1 and OgeuIscB. Utilizing protein language models to optimize ZFPs designed by modular assembly further simplifies the development of zmBEs. Leveraging these methodologies, we engineer a zmBE that effectively induces the SMN2 exon 7 T:A(6) > C:G conversion, restores the exon 7 inclusion, and improves spinal muscular atrophy in a murine model after being delivered via a single AAV vector. Our study provides a versatile platform for developing miniature base editors for in vivo therapeutic applications.

BACKGROUND: An understanding of the natural history and progression of spinal muscular atrophy (SMA) in untreated children, is crucial for the identification of responsive outcome measures that are used to demonstrate the effectiveness of disease-modifying therapies (DMTs). However, there have been no such studies from India. OBJECTIVES: This retrospective registry-based study was aimed at outlining the progression of type 2 SMA among children, with a median age of ten years, over a span of two years. METHODOLOGY: Data from 30 drug-naïve children diagnosed with type 2 SMA were included in the study. A semi-structured pre-tested proforma was used to collect the baseline characteristics of the participants. The outcome variables were the neuromotor function scores based on Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and the motor milestones established by the World Health Organization (WHO) modified to include attainment of head control. RESULTS: At the one-year follow-up, clinically relevant decrements in HFMSE and RULM scores were noted in 52% and 26% of the patients, respectively. After two years, these figures rose to 67% and 37%, respectively, suggesting an earlier loss of function of the lower extremities in these children compared to the upper extremities. Motor milestone loss was not observed in any of the children. Swallowing difficulty was significantly associated with a decrease in the HFMSE score. At the end of the two-year follow-up period, the cumulative survival was found to be 0.88, and the mean survival time was estimated to be 29 months. CONCLUSION: Our results align with earlier studies indicating that disease progression in type 2 SMA varies among children, highlighting its heterogeneous nature.

The combined newborn screening program for Spinal Muscular Atrophy (SMA) and Severe Combined Immunodeficiency (SCID) was evaluated in Liguria through a five-year pilot study involving 32,289 newborns. A single multiplex real-time PCR assay on dried blood spots enabled simultaneous detection of SMN1 exon 7 deletions and quantification of T-Cell Receptor Excision Circles (TREC) and Kappa-Deleting Recombination Excision Circles (KREC), achieving near-complete population coverage and a low recall rate. Ten newborns received a confirmed diagnosis of a targeted condition: five newborns were diagnosed with spinal muscular atrophy (SMA), of whom four were treated presymptomatically and achieved favorable clinical outcomes, whereas one with SMA type 0 died a few days after birth. Five newborns were diagnosed with immunodeficiencies, including two cases of adenosine deaminase (ADA)-related severe combined immunodeficiency (SCID), and three clinically significant secondary findings (idiopathic T-cell lymphopenia, DiGeorge syndrome, and transient B-cell lymphopenia). No false-negative cases were observed during follow-up. The TREC and KREC profiles were consistent with the underlying immunological diagnoses. Overall, the study demonstrates that combined SMA and SCID newborn screening is feasible, reliable, and clinically impactful, supporting its integration into public health screening programs.

Polyglutamine diseases are primarily age-dependent neurodegenerative disorders, but patient-based data also point to a broader, multisystem biology. Clinical, imaging, biochemical, and post-mortem studies support peripheral involvement across multiple organ systems in the onset and progression of Huntington's Disease, Spinal and Bulbar Muscular Atrophy, Dentatorubral-Pallidoluysian Atrophy, and six Spinocerebellar Ataxias. Various peripheral abnormalities often emerge before or alongside overt neurological symptoms, contribute to disability and mortality, and are only partly explained by deconditioning or medications. Current data support viewing polyglutamine diseases as systemic protein-misfolding syndromes with organ-selective vulnerability, where peripheral tissues both mirror and modify CNS pathology in humans. Here, we propose that integrated, longitudinal, multisystem phenotyping and targeted organ-directed interventions are essential components of future research investigations, clinical care, and trial design.

INTRODUCTION: Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by progressive axial and proximal limb weakness, often leading to ventilatory insufficiency. Risdiplam, an oral SMN2 splicing modifier, has demonstrated efficacy across clinical trials involving both infantile and late-onset SMA. However, real-world data on its long-term safety and effectiveness remain limited. OBJECTIVE: To evaluate the safety and preliminary efficacy of Risdiplam after one year of treatment in patients with SMA types 2 and 3. METHODS: This retrospective, single-center study included patients with genetically confirmed SMA treated with Risdiplam at the Neuromuscular Clinic of the Hospital das Clínicas, University of São Paulo, Brazil. All participants were treatment-naïve before initiating Risdiplam and were followed for 12-months. Motor function (CHOP-INTEND, HFMS), pulmonary function (FVC, FEV₁), and necessity of G-tube were assessed at baseline, 6 m, and after one year of therapy. RESULTS: Sixteen patients were included (mean age 20-years, range 6-56). Eleven patients (69%) had SMA type 2, while 5 (31%) had SMA type 3. The mean untreated disease duration was 18-years (range 5-44). After 12-months, 13-patients (81%) showed apparent stabilization or improvement in motor function, while 3 (19%) exhibited motor decline. Pulmonary function improved or stabilized in 13 patients (81%) and declined in 3 (19%). Clinical decline was observed in patients with progressive scoliosis or overweight. All patients maintained exclusive oral feeding. CONCLUSION: Preliminary data from the one-year follow-up suggest that Risdiplam is safe and appears generally effective in preserving or enhancing motor, respiratory, and swallowing functions. Patients with severe skeletal deformities exhibited less favorable outcomes.