Premature infants suffering from drug -resistant crises responds to oligonucleotide antissens treatment

The researchers led by Ludwig-Maximilians-Universität München induced a reduction greater than 60% of the frequency of crises in a premature infant with a encephalopathy of development and epileptic SCN2A early (DEE). The crises initially occurred at a rate of 20 to 25 an hour and fell five to seven per hour after the intrathecal dosage repeated with Elsunersen, an Oligonucleotide Antisens therapy.

SCN2A is a gene that codes for the Sedic Tension Channel Nav1.2, which is mainly expressed in the excitatory neurons of the central nervous system. This channel plays a key role in potential generation and propagation of action. The variants of SCN2A are associated with a wide spectrum of neurodevelopmental disorders, depending on whether the variant causes loss of function or a function gain effect.

Mutations of loss of function in SCN2A are linked to epilepsy with a subsequent start and, in some cases, to autism spectrum disorders without crises. The function gain variants are associated with more serious phenotypes, including development encephalopathies and early early (DEE).

In these cases, convulsions generally start in the first three months of life and are accompanied by significant development delays. Sedic channel blockers can reduce the frequency of crises, but generally offer a limited advantage to cognitive or engine development.

The antisen oligonucleotides (ASOS) are short nucleic acid shutters designed to bind to specific RNA targets and reduce the expression of genes. ASOs have become a desired therapeutic class promising to target specific genetic mechanisms.

Preclinical studies using SCN2A function gain models have shown that ASOS can reduce the expression of SCN2A mRNA and a lower crisis charge. Since the SCN2A gene is highly sensitive to the dose, a targeted reduction requires meticulous calibration to avoid the harmful effects of the sub or an overexpression.

In the study, “Treatment of antisen oligonucleotides in a premature infant with scn2a encephalopathy and epileptic encephalopathy” Nature MedicineThe researchers carried out a single patient clinical intervention to assess the safety and therapeutic potential of Elsunersen, an antissens Gapmer oligonucleotide targeting scn2a mRNA.

The patient was a premature woman born at 29 weeks and four days of gestation, diagnosed with SCN2A-DEE at early on the basis of clinical presentation and genetic tests. The crises began the first postnatal day and persisted despite a combination of conventional antiserze drugs.

At 7 weeks, the treatment started with the administration of Elsunersen via the lumbar puncture, providing the drug in the cerebrospinal fluid surrounding the spinal cord.

To assess the effect of the drug on the dysfunction of sodium channels, the team used computer structural modeling and in vitro electrophysiological tests. Tension-clamp recordings and dynamic action potential clamping protocols have confirmed the inactivation of altered channels and an increase in persistent sodium current.

Pharmacokinetic modeling estimated the distribution and retention of drugs in cerebrous and brain tissue. The frequency of crises and clinical responses were followed throughout the treatment period.

The crisis activity was initially reactive to nine different conventional anti -aged drugs, including phenobarbital, levetiracetam, phenytoin and midazolam. Eight days after the first intrathecal dose of Elsunersen, intermittent ruptures of the epilepticus status (several crises without recovery between the episodes) were observed. Subsequent doses have led to a complete end of the epileptic status and a sustained reduction in the frequency of crises.

In 12 weeks, the cumulative dosage reached 2.5 mg on three administrations. The frequency of crises decreased by an average of 19.7 per hour to 6.6 per hour, which represents a reduction of 67%. After seven total doses during the initial treatment phase, the monthly dosage continued with ten additional administrations of 8 mg. Crisis control remained stable at five to seven per hour, especially after phenytoin at the age of 14 months.

Parents reported an increase in the severity and frequency of crises of approximately four to six weeks after each administration, a scheme supported by pharmacokinetic modeling. These observations informed the dosage interval. Throughout the processing course, no serious or serious adverse event has been reported.

Vital signs, blood panels and heart assessments have shown no anomaly attributable to treatment. No hydrocephalus or complications related to antissens oligonucleotide has been observed.

During the final follow -up at 22 months, the frequency of crises remained from five to seven per hour, with a monthly dosage in the course of Elsunersen.

The results suggest a causal relationship between dosage intervals and crisis control, as supported by pharmacokinetic modeling and crisis recurrence four to six weeks after administration. Researchers offer that crisis control can be maximized by combining ASO treatment with sodium channel blockers to adjust neural excitability.

In a case where several conventional therapies have failed, the treatment with Elsunersen has succeeded. Preclinical studies had already established a mechanistic justification to target SCN2A transcripts with antissens oligonucleotides, which makes the expected and yet extraordinary results. As a single case, a broader evaluation of Elsunersen safety, dosage requirements and generalization will require formal clinical trials.

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