V.S. Kakaulina

Coagulation factor VIII (FVIII) is a key therapeutic protein for hemophilia A, an inherited bleeding disorder caused by FVIII deficiency or dysfunction. The development and production of FVIII-based therapeutics remains challenging due to the intrinsic complexity of FVIII biosynthesis, folding, secretion, and functional stability. Advances in the understanding of the FVIII life cycle, as well as studies of its natural homologs, have created opportunities to develop improved FVIII variants. In parallel, therapeutic strategies to restore FVIII activity have evolved from replacement therapy with exogenous FVIII to gene-based delivery of a functional F8 copy. Among these approaches, AAV-mediated gene therapy has emerged as a clinically viable platform with a generally favorable safety profile, prompting the development of multiple therapeutic candidates for hemophilia A. This review summarizes established and current knowledge of FVIII structure, biosynthesis, and immunology in the context of developing effective and clinically applicable AAV-mediated therapies for hemophilia A. Particular attention is given to engineered FVIII variants and the latest clinical findings in AAV gene therapy, as well as to long-term efficacy and safety.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare, autosomal recessive neurodegenerative disorder caused by mutations in the TPP1 gene, which lead to a decrease or complete loss of lysosomal tripeptidyl peptidase 1 enzyme activity. The classic form of CLN2 disease typically manifests between the ages of 2 and 4 years. Over time, there is a rapid and predictably severe progression of intellectual and motor deficits, loss of visual acuity, and an increased frequency of epileptic seizures refractory to antiepileptic therapy. In its natural course, the classic form of CLN2 disease leads to severe disability by 6–7 years of age and death on average during the 10th year of life. Currently, pathogenetic enzyme replacement therapy has been developed only for CLN2 disease, utilizing the drug cerliponase alfa. In Russia, children with CLN2 disease are provided with cerliponase alfa through funding from the “Circle of Kindness”, a state fund supporting children with severe life-threatening and chronic diseases, including rare (orphan) conditions. Cerliponase alfa cannot cross the blood-brain barrier and must be administered directly into the cerebrospinal fluid via intracerebroventricular (ICV) infusion through a surgically implanted reservoir and ventricular catheter. Infectious complications can result in missed ICV infusions, which, in turn, may adversely affect the efficacy of enzyme replacement therapy. To reduce the risk of infectious complications, strict adherence to aseptic rules is essential during patient preparation, as well as during and after the ICV infusion. These practical guidelines for performing ICV infusions of enzyme replacement therapy in patients with CLN2 disease have been developed to implement measures in clinical practice aimed at minimizing the risk of infectious complications and damage to ICV infusion devices.

Objective. To assess the efficacy and safety of onasemnogene abeparvovec (OA) in children with spinal muscular atrophy (SMA) treated between 2021 and 2025 at a Moscow regional rare disease referral center (Morozov Children’s City Clinical Hospital). Material and methods. This study included 20 children with a confirmed diagnosis of 5q spinal muscular atrophy (SMA). Safety was evaluated in all 20 patients for up to 3.5 years following treatment, with adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Efficacy was analyzed in 16 patients at 8 to 37 months post-injection. Motor function was assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), while general motor development was evaluated using the Hammersmith Infant Neurological Examination, Section 2 (HINE-2). Key motor milestones were compared to established World Health Organization (WHO) norms. Data was analyzed by stratifying patients into two groups: those identified through expanded newborn screening (Group 1) and those diagnosed via high-risk screening (Group 2). Results. In Group 1, the mean age at treatment initiation was 1.9 (1.4—2.8) months, with a mean weight of 4.8 (3.7—6.25) kg. In Group 2, the mean age at treatment was 14.8 (5.5—47) months, with a mean weight of 9 (6—13.7 )kg. Within one week post-OA administration, most patients (19/20) experienced clinical symptoms, including hyperthermia (Group 1: 8/9; Group 2: 10/11), increased regurgitation/vomiting (Group 1: 5/9; Group 2: 6/11), and decreased appetite/refusal to feed (Group 1: 3/9; Group 2: 9/11). These symptoms were more severe in Group 2, requiring intravenous and symptomatic therapy, nasogastric tube placement, and parenteral nutrition in some cases. Grade 1—2 thrombocytopenia (CTCAE v.5) was observed one week post-OA in three patients from Group 2. Elevated hepatic transaminases were observed in 16/20 children: Group 1 — 6/9 (66%), Group 2 — 10/11 (90%). In Group 1, all children experienced Grade 1 elevations (CTCAE v.5), while in Group 2, 6 children had Grade 1 elevations (54%), 2 had Grade 2 (18%), 1 had Grade 3 (9%), and 1 had Grade 4 (>20x ULN) (9%). Asymptomatic troponin I elevations were recorded in 6 children from Group 1 and 4 from Group 2. The median duration of prednisolone administration was 13 weeks (8—24) in Group 1 and 21 weeks (12—42) in Group 2. In Group 1, the mean CHOP INTEND score increased by 11.5 at 4 months, the HINE-2 score increased by 10.5 points at 4 months and 15.5 points at 6 months from baseline; all children achieved main motor milestones according to WHO norms. In Group 2, the mean CHOP INTEND score increased by 4 at 6 months and 7.2 points at 12 months from baseline; the HINE-2 score increased by 2.3 points at 6 months and 4.7 points at 12 months from baseline; five children improved their functional status, and 6/9 children acquired new motor skills. Conclusion. This study presents the findings of a long-term assessment of the efficacy and safety profile of drug OA in pediatric patients across various age groups and functional ability levels, including individuals identified through expanded newborn screening. Younger patients exhibited a significantly lower incidence of adverse events and demonstrated superior therapeutic efficacy. The majority of older children experienced either positive progression or stabilization of their condition, outcomes that were largely contingent upon their initial functional status and the duration of the pre-treatment waiting period.

Phenylketonuria (PKU) is a common inherited metabolic disorder characterised by impaired metabolism of the amino acid phenylalanine. The disease results from a mutation in the phenylalanine hydroxylase (PAH) enzyme, which converts phenylalanine (Phe) into tyrosine (Tyr). The absence or inactivity of this enzyme results in significantly elevated levels of Phe in the blood, which can lead to severe neurological conditions, including intellectual disability, epilepsy, and other developmental disorders. Since its discovery, animal models have played a crucial role for understanding the pathophysiology of PKU, as well as providing recognisable proof of targets and surveying new remedial specialists and in vivo medicines. In the present study, we conducted a comprehensive review of the experimental and non-experimental animal models employed for phenylketonuria and its associated complications.

Nowadays, Dravet syndrome is one of the most studied forms of genetic epilepsy. Despite a large number of studies and publications, Dravet syndrome remains a difficult neurological disease to treat. The relationship of epileptogenesis in Dravet syndrome with the activity of sodium channels has been studied, and data on the different effectiveness and ineffectiveness of anticonvulsant drugs with different mechanisms of action have been obtained. Drugs that modify neural transmission, enhance inhibitory transmission, and reduce excitatory transmission, as well as their combination, are more effective. Drugs that reduce the effect of inhibitory transmission (in particular, sodium channel blockers) should not be used. In our opinion, the correct choice of therapy for Dravet syndrome associated with a mutation in the SCN1A gene is possible only from the perspective of understanding the work of neural channels in the brain.

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder typically manifesting in boys aged 2–5 years, characterized by a progressive course. According to natural disease progression data, individuals with DMD typically lose the ability to walk independently by the age of 13. In most cases, the disease leads to cardiorespiratory complications, resulting in a lethal outcome between the ages of 20–30.In recent years, there have been therapeutic agents developed for the pathogenic treatment of this condition. One such medication is ataluren (Translarna®), used in patients with DMD caused by the formation of a “stop codon” (nonsense mutation) in the DMD gene, responsible for the development of the disease.This article presents the experience of applying ataluren (Translarna®) in boys residing in Moscow who suffer from Duchenne muscular dystrophy.

A timely detection of patients with tetrahydrobiopterin (BH₄) -deficient types of hyperphenylalaninemia (HPABH₄) is important for assignment of correct therapy, allowing to avoid complications. Often HPABH₄ patients receive the same therapy as phenylalanine hydroxylase (PAH) -deficiency (phenylketonuria) patients—dietary treatment—and do not receive substitutive BH₄ therapy until the diagnosis is confirmed by molecular genetic means. In this study, we present a cohort of 30 Russian patients with HPABH₄ with detected variants in genes causing different types of HPA. Family diagnostics and biochemical urinary pterin spectrum analyses were carried out. HPABH₄A is shown to be the prevalent type, 83.3% of all HPABH₄ cases. The mutation spectrum for the PTS gene was defined, the most common variants in Russia were p.Thr106Met—32%, p.Asn72Lys—20%, p.Arg9His—8%, p.Ser32Gly—6%. We also detected 7 novel PTS variants and 3 novel QDPR variants. HPABH₄ prevalence was estimated to be 0.5–0.9% of all HPA cases in Russia, which is significantly lower than in European countries on average, China, and Saudi Arabia. The results of this research show the necessity of introducing differential diagnostics for HPABH₄ into neonatal screening practice.

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