Personalized Gene Therapy Promising in Rare Epilepsy

Personalized gene therapy targeting the genetic cause of SCN2A-related developmental and epileptic encephalopathy (DEE) reduced seizures and was associated with developmental gains in two boys with severe, treatment-resistant disease, researchers reported.Seizure frequency fell by an estimated 26% in one patient and 90% in the other. Both patients experienced prolonged seizure-free periods, reduced their use of antiseizure medications, and showed improvements in communication, motor skills, behavior, and other areas of functioning.“We’ve seen changes across the board, showing that targeting the root genetic cause can produce measurable improvement,” principal investigator Olivia Kim-McManus, MD, with UC San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine in San Diego, said in a statement.The findings were published online on July 21 in Nature Medicine.Targeting the Mutant Gene CopySCN2A-related DEE is a rare, severe form of childhood epilepsy. SCN2A disorders are also among the most common monogenic causes of autism.The condition is caused by mutations in the SCN2A gene, which encodes a sodium channel involved in controlling the flow of sodium ions into neurons.Certain mutations increase neuronal excitability, resulting in uncontrolled seizures as well as developmental delays, autism, movement abnormalities, and gastrointestinal problems. Current treatment is largely symptomatic, and antiseizure medications are often ineffective.Kim-McManus and colleagues treated two boys, aged 9 and 14 years, using allele-selective antisense oligonucleotides (ASOs) tailored to each child’s genetic profile. The therapies were designed to reduce production of the disease-causing SCN2A transcript while preserving expression of the healthy copy of the gene.The ASOs were administered by intrathecal injection, with doses generally repeated every 2-3 months and adjusted according to the patients’ clinical response.Improved OutcomesThe younger patient had neonatal-onset epilepsy, approximately 30 seizures per month at baseline, and had previously received more than 10 antiseizure medications.During 24 months of follow-up, his percentage of seizure-free days increased from 57.8% to 66.5%, corresponding to an estimated 26% reduction in seizures, although the reduction was not statistically significant (P = .286).He was also able to discontinue phenytoin, which he had required since infancy.The older patient had experienced infantile spasms and multiple refractory seizure types and had been referred to hospice at age 2 years.During 16 months of follow-up, ASO therapy was associated with an estimated 90% reduction in daily seizures (P < .001). The proportion of seizure-free days increased from 0% before treatment to 46% afterward, and he went for periods exceeding 2 months without requiring emergency rescue medication.Developmental GainsDevelopmental changes were also observed in both patients. The younger child showed gains in language, communication, fine and gross motor skills, sensory processing, and behavior.The older patient had improvements in communication, irritability, ataxia, and motor function. Most notably, despite previously being unable to walk, he achieved independent gait at the age of 15 years.Kim-McManus told Medscape Medical News the walking milestone occurred after three doses of the genetic therapy and was unexpected.“Independent gait has been sustained over the course of the trial and suggests that there are critical windows of development but that there can be continued brain plasticity and potential developmental gains which persist through childhood and adolescence,” she explained.The older patient’s severe gastrointestinal symptoms also improved, with more regular bowel movements and less need for suppositories.Both therapies were well tolerated, with no treatment-related serious adverse events, abnormal laboratory findings, or clinically significant changes on ECG or EEG.Potential to Treat More PatientsThe investigators said long-term follow-up is needed to determine the durability of the safety and efficacy findings. They also noted that some disease effects may be less reversible when treatment begins later, suggesting that early genetic diagnosis and intervention could maximize the benefit.The allele-selective ASOs developed for the two patients might also be usable in other patients with SCN2A variants who carry the same relevant single-nucleotide polymorphism configuration.Among 19 additional patients with SCN2A-related disorders identified through rapid whole-genome sequencing, three (16%) had a genetic configuration that could potentially be targeted by the ASO developed for the older patient, supporting a possible path from single-patient treatment to broader use in genetically compatible patients, the researchers said.Kim-McManus said funding and regulatory support are among the main challenges to expanding this approach to more patients in a broader clinical trial. She is working on tackling these obstacles in collaboration with nonprofit and other entities in the hopes of bringing genetic therapies to more patients with rare disease.The study was funded, in part, by a grant from the California Institute for Regenerative Medicine. Author disclosures are available with the original study publication.