Short-Term Safety and Efficacy of Onasemnogene Abeparvovec in 10 Patients with Spinal Muscular Atrophy: Cohort Study

Background. The efficacy and safety of onasemnogene abeparvovec have been demonstrated in patients with spinal muscular atrophy (SMA) in several clinical and observational studies. Gene replacement therapy results in Russian patients with SMA is not investigated yet.Objective. The aim of the study is to study the safety and efficacy of onasemnogene abeparvovec in children with SMA in real clinical practice.Methods. The study included patients with proximal 5q SMA administered with onasemnogene abeparvovec. Diagnosis was verified by biallelic deletion in the 7th exon of the SMN1 gene. Gene replacement therapy was administered according to the decision of neurologists consensus in case of the absence of antibodies to the adeno-associated serotype 9 virus. The therapy safety was estimated via clinical and laboratory data from the hospital (at least 7 days) and from outpatient departments (at least 60 days). Efficacy was estimated via CHOP INTEND scale and mastering new motor skills ≥ 6 months after therapy onset.Results. Treatment outcomes were studied in 10 SMA patients aged 19 months (15; 21). All patients developed at least one clinical manifestation (hyperthermia, vomiting, lethargy and/or loose stool) associated with drug administration during the first week of follow-up. Increased hepatic transaminases activity and monocytosis was recorded in all patients, thrombocytopenia — in 9, neutropenia — in 5, increased troponin I concentration — in 3. In three cases it was necessary to increase the oral prednisolone dose of to 2 mg/kg, in one case — the dexamethasone pulse therapy dose. The therapy efficacy was monitored ≥ 6 months after therapy onset via the CHOP INTEND scale in 2 patients (scores increased by 32 and 19 points, respectively), and via mastering new motor skills in 8 patients (positive dynamics was noted in 7 cases).Conclusion. The onasemnogene abeparvovec is relatively safe and quite effective for using in real clinical practice

Evaluation for Retinal Therapy for RPE65 Variation Assessed in hiPSC Retinal Pigment Epithelial Cells

Human induced pluripotent stem cells (hiPSCs) generated from patients and the derivative retinal cells enable the investigation of pathological and novel variants in relevant cell populations. Biallelic pathogenic variants in RPE65 cause early-onset severe retinal dystrophy (EOSRD) or Leber congenital amaurosis (LCA). Increasingly, regulatory-approved in vivo RPE65 retinal gene replacement therapy is available for patients with these clinical features, but only if they have biallelic pathological variants and sufficient viable retinal cells. In our cohort of patients, we identified siblings with early-onset severe retinal degeneration where genomic studies revealed compound heterozygous variants in RPE65, one a known pathogenic missense variant and the other a novel synonymous variant of uncertain significance. The synonymous variant was suspected to affect RNA splicing. Since RPE65 is very poorly expressed in all tissues except the retinal pigment epithelium (RPE), we generated hiPSC-derived RPE cells from the parental carrier of the synonymous variant. Sequencing of RNA obtained from hiPSC-RPE cells demonstrated heterozygous skipping of RPE65 exon 2 and the introduction of a premature stop codon in the mRNA. Minigene studies confirmed the splicing aberration. Results from this study led to reclassification of the synonymous variant to a pathogenic variant, providing the affected patients with access to RPE65 gene replacement therapy.

Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

Narcolepsy Treatment: Present and Future

Narcolepsy is a chronic, disabling sleep disorder with a significant diagnostic delay. Nowadays, treatment is focused on managing symptoms that impacts patient’s life, such as at workplace, social events or even at school, but not aimed cure the disease. However, we have pharmacological treatments that effectively help control the main symptoms (excessive daytime sleepiness, cataplexy, fragmentation of nocturnal sleep, sleep paralysis and hypnagogic and hypnopompic hallucinations). On the other hand, pharmacological treatment must be individualised as there are great variations in severity, order of appearance symptoms and development of the disease. We intend to expose the different symptomatic treatments recommended by clinical guidelines and the clinical management from a practical point of view. Future treatments include therapies based on the replacement of hypocretin or the administration of agonist receptors. Other techniques such as hypothalamic stem cell transplantation, gene replacement therapy or immunotherapy are also being investigated.