Perspectives of the Friedreich ataxia community on gene therapy clinical trials.

Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies.

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Polysomnography findings in children with spinal muscular atrophy after onasemnogene-abeparvovec.

BACKGROUND: Sleep disordered breathing (SDB) is common in patients with neuromuscular diseases, including spinal muscular atrophy (SMA). While polysomnography (PSG) findings have been described in natural history studies of patients with SMA, reports regarding PSG in treated children are limited to nusinersen. We aim to describe the sleep characteristics in a cohort of children treated with Onasemnogene-abeparvovec. METHODS: We conducted a cross-sectional cohort study of children with SMA followed at the University of Florida Center for neuromuscular and rare diseases and had a diagnostic or split night PSG after SMA treatment. RESULTS: Eight children were included in the cohort (four female), aged 5-250 days at diagnosis. Five children had two survival motor neuron 2 (SMN2) copies, two had three SMN2 copies and one subject had four SMN2 copies. Median age at the time of treatment was 46.5 days (range 20-257). All children received onasemnogene-abeparvovec (OA) before their PSG; in addition to OA, one received nusinersen and one received risdiplam. Apnea hypopnea index (AHI) ranged from 3.6 to 24.1/h. REM AHI was higher than NREM AHI. Median Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP-Intend) score at the time of PSG was 55 (range 33-64). There was no correlation between age at treatment, CHOP-Intend score and AHI. CONCLUSION: SDB is common in treated children with SMA, regardless of age at diagnosis, treatment and neuromotor scores. While AHI may not be the only indicator of SDB in this population, indications, timing of PSG in this cohort remain unknown.

Cardiac and clinical phenotype in Barth syndrome.

OBJECTIVE: Barth syndrome, an X-linked disorder that is characterized by cardiomyopathy, neutropenia, skeletal myopathy, and growth delay, is caused by mutations in the taffazin gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. The clinical phenotype in Barth syndrome has not been characterized systematically, and the condition may be underrecognized. We sought to evaluate extent of cardioskeletal myopathy, potential for arrhythmia, delays in growth, and biochemical correlates of disease severity in patients with this disorder. METHODS: We conducted an observational, cross-sectional study of the largest cohort of patients with Barth syndrome to date (n = 34; age range: 1.2-22.6 years). Evaluation included echocardiography, electrocardiography (standard and signal-averaged), microvolt T wave alternans analysis, biochemical and hematologic laboratory analyses, and physical therapy evaluation of skeletal myopathy. RESULTS: Family history was positive for confirmed or suspected Barth syndrome in 63%. Ninety percent of patients had a clinical history of cardiomyopathy (mean age at diagnosis of cardiomyopathy: 5.5 months; at genetic confirmation of Barth syndrome: 4.6 years). Echocardiography revealed a mean ejection fraction of 50% +/- 10%, mean fractional shortening of 28% +/- 5%, and mean left ventricular end-diastolic volume z score of 1.9 +/- 1.8. Left ventricular morphology demonstrated increased trabeculations or true noncompaction in 53%. Of 16 patients who were evaluated at > or = 11 years of age, 7 (43%) had documented ventricular arrhythmia. Growth deficiency was present (mean weight percentile: 15%; mean height percentile: 8%). Laboratory analysis revealed low total white blood cell count (absolute count: < 4000 cells per microL) in 25% of those who were not on granulocyte colony-stimulating factor. Hypocholesterolemia was present in 24%, decreased low-density lipoprotein cholesterol in 56%, low prealbumin in 79%, and mildly elevated creatine kinase in 15%. CONCLUSIONS: Our cohort demonstrated clinical variability, but most had cardiomyopathy and diminished growth velocity, with a propensity toward neutropenia and low cholesterol. There was increased incidence of ventricular arrhythmia, predominantly in adolescents and young adults. Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance.