A team of researchers from the University School of Medicine recently studied the use of a new gene therapy treatment called TANGO to treat Dravet syndrome, a severe form of epilepsy. Their proposal would increase levels of a gene called SCN1Awhich provides instructions for sodium channels.
Dravet syndrome was first identified by French epileptologist Charlotte Dravet in 1978. It affects around 35,000 people in the United States, Canada, Japan, France, United Kingdom and Germany.
Asst. Neurology professor Erika Axeen said Dravet syndrome can have a wide variety of symptoms.
“Dravet syndrome is a rare genetic epileptic and developmental encephalopathy with symptoms appearing within the first year of life,” Axeen said in an email to Cavalier Daily. “These children often have seizures that do not respond to typical anti-epileptic drugs. Along with this, they may have varying degrees of developmental delay and may have intellectual disability.
The seizures that result from Dravet syndrome usually last longer than five minutes and are frequently drug resistant.
According to Eric Wengert, a postdoctoral fellow at Children’s Hospital of Philadelphia, symptoms of Dravet syndrome can extend beyond the syndromes. Indeed, up to 20% of people diagnosed with Dravet syndrome do not survive to adulthood.
“Dravet syndrome is a severe genetic epilepsy syndrome that is quite rare [and occurs] in [out of] 16,000 people,” Wengert said in an emailed statement to the Cavalier Daily. “Patients not only have seizures, but they also have cognitive impairment, movement disorders, and other challenging comorbidities.”
The severity of Dravet syndrome lies in its drug resistance, which means that patients and their families face a substantial risk of seizures and seizure-induced sudden death.
“This drug-resistant aspect of Dravet syndrome has led to great efforts by various research teams to identify new treatment strategies, as evidenced by the fact that many new drugs have been approved since 2018,” said said Wengert.
About 85 percent of people diagnosed with Dravet syndrome have a SCN1A gene mutation. Mutated versions of SCN1A lead to inefficient sodium channels in the brain. These malfunctions lead to irregular neural activity like seizures.
The research team, consisting of Wengert, Asst. Professor of Anesthesiology Manoj Patel and Ian Wenker, a research associate at the School of Medicine, have mainly sought to reduce the harmful effects of the mutated SCN1A gene, thereby limiting the frequency and occurrence of seizures.
“The novel gene therapy approach we investigated in the study is specifically designed to increase SCN1A levels to correct the deficits known to cause most cases of Dravet syndrome,” Wengert said. “85% of patients with Dravet syndrome have an altered SCN1A gene that does not make a functional protein.”
The team collaborated to study the potential of gene therapy as an alternative treatment method for patients with Dravet syndrome by restoring interneurons, missing proteins in nerve cells. Using a particular gene therapy treatment called TANGO – Targeted Augmentation of Nuclear Gene Production – designed to stimulate SCN1A, the team was able to induce an increase in protein production in mice.
“One of the reasons TANGO is particularly exciting as a new treatment strategy is that it directly addresses the genetic cause of Dravet syndrome – the loss of functional SCN1A,” Wengert said. “Because TANGO is a highly targeted gene therapy, the risk of side effects from the treatment is considered minimal compared to other currently available treatments.”
This innovative therapeutic approach was very effective in reducing seizure frequency in the mouse model of Dravet syndrome.
“After weaning, 10 of 11 mice that did not receive TANGO had seizures, while only 2 of 13 mice treated with TANGO had seizures,” Wengert said. “Because the mice had fewer seizures, TANGO treatment also significantly prolonged the survival of mice with Dravet syndrome.”
These findings have implications for the future of gene therapy as a therapeutic approach and potential standard of care for patients with Dravet syndrome. The team’s work was recently published in “brain research”, although further clinical studies are needed to verify the promising preclinical work published by researchers at the University.
“The hope is that TANGO may be able to alter the expression of SCN1A mRNA in a meaningful way, which may reduce seizures, reduce the risk of SUDEP, and hopefully impact delays. developmental and cognitive outcomes in this patient population,” Axeen said.
Wengert is optimistic that this treatment will become convenient and accessible in the future.
“[We hope to] support the development of new treatments for Dravet syndrome so that patients and their families have access to better treatment options,” Wengert said.
However, gene therapy research does not stop there. Extensive experimental research is still needed to study TANGO for Dravet syndrome, and clinical trials are underway.
“The clinical data will provide much-needed information about whether TANGO can actually benefit humans with Dravet syndrome,” Wengert said.