Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial

Abstract

Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

“…Currently, a number of clinical trials are investigating different disease‐modifying treatment options for MPS IIIA, including gene therapy and high‐dose synthetic genistein 14, 15. The prediction of untreated disease progression (in RP or SP patients) is crucial for the inclusion of patients in trials, as the assessment of treatment effects must be related to the expected natural history of the disease.…”

“…However, new missense mutations are frequently reported, hampering the early assessment of phenotypic severity in these patients 12, 13. As a disease‐modifying treatment of MPS IIIA is imminent, with gene therapy now in trials,14, 15 early diagnosis will be paramount, for example, by newborn screening (NBS), to allow timely initiation of treatment. Early assessment of the phenotype, even before the onset of clinical signs and symptoms, will thus be crucial both for the selection of patients for trials and for the assessment of treatment effects.…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Two other clinical trials have tested AAV vectors carrying mammalian promoters such as the mouse phosphoglycerate kinase (PGK) promoter [120], or the rat neuron-specific enolase (NSE) promoter [121]. The choice of promoters is based on the availability of extensive data from pre-clinical studies in different animal models showing that AAV-mediated transgene expression under these promoters is stable and long lasting in the mammalian brain [122][123][124][125][126][127].…”

Neuronopathic Types of Mucopolysaccharidoses: Pathogenesis and Emerging Treatments

“…По данным нейропсихологического исследования отмеча-лось незначительное улучшение показателей поведения, внимания и сна; данные магнитно-резонансной томо-графии показали нарастание атрофии головного мозга у 2 пациентов и отсутствие динамических изменений у 2 других детей. Наибольший положительный эффект на нейрокогнитивные характеристики продемонстрирован у самого младшего пациента [46]. C целью уточнения отда-ленного эффекта, а также безопасности ранее проведен-ной генной терапии наблюдение за данными пациентами продолжается (NCT02053064) [29].…”