Shelley W. Collins

Pompe disease gene therapy

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

B-Cell Depletion and Immunomodulation before Initiation of Enzyme Replacement Therapy Blocks the Immune Response to Acid Alpha-Glucosidase in Infantile-Onset Pompe Disease

OBJECTIVE To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.

Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity.

ABSTRACT Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid &agr;‐glucosidase (GAA). Children with infantile‐onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1‐CMV‐GAA) to treat respiratory neural dysfunction in infantile‐onset Pompe. Subjects (aged 2–15 years, full‐time MV: n = 5, partial/no MV: n = 4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1‐CMV‐GAA to the diaphragm with continued exercise. Since AAV‐mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1‐CMV‐GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1‐CMV‐GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p < 0.05 to p < 0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180 days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p < 0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1‐CMV‐GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains. HighlightsChildren with Pompe disease and ventilatory insufficiency received AAV1‐CMG‐GAA.Exercise alone did not change respiratory muscle function in any subjects.In less‐affected children, dynamic respiratory function improved after gene therapy.

Transition of care: What Is the pediatric hospitalist's role? An exploratory survey of current attitudes†

OBJECTIVE Survey of current attitudes of pediatric hospitalists related to transition of care. METHODS We developed and piloted a survey that was validated by an expert on transition. It was introduced it to the AAP/Pediatric Hospital Medicine Listserv using Survey Monkey(TM). Any participant who agreed to the informed consent was included in the survey. RESULTS Patients aged 16-17 with chronic medical conditions were taken care of by pediatric hospitalists 70% of the time. Patients aged 18-20 were cared for by pediatric hospitalists 36.8% of the time. Advantages of hospitalist participation in healthcare transition include improved continuity of care and quality of care. The biggest impediments might be lack of time and resources. Most surveyed would be interested in a web based educational module to develop their understanding of healthcare transition. CONCLUSION The survey provides a snapshot of current attitudes of pediatric hospitalist involvement in transition of care. Pediatric hospitalists are interested in participating in healthcare transition. Although more research is needed to compare current models of transition services and a hospitalist model, the perception for inpatients is that better quality of care can be expected. Targeted educational modules might provide a foundation for pediatric hospitalists to build their scope of practice to include transition services.