Imagine your 5-month-old baby daughter starts to experience intense, prolonged convulsive seizures. These seizures are distressing to witness and as a parent you feel helpless. Not knowing what causes them only adds to the fear. After a harrowing wait, you finally receive a diagnosis: Dravet syndrome, a rare, severe form of epilepsy that threatens your child’s development and quality of life. You are faced with the reality that your child will likely need multiple, life-long antiseizure medications. These drugs can carry harsh side effects and yet uncertainties remain. Will her symptoms be controlled? What will her future look like? How will you, as a family, cope?
For the 1 in 15,700 people with Dravet Syndrome and their loved ones, such questions are not hypothetical. So, to honour Epilepsy Awareness Month this November, at TVF we wanted to shine a light on this devastating, intractable form of epilepsy: what is known, what is unknown, and how gene therapy might transform the therapeutic landscape.
The situation today
Dravet Syndrome was described in 1978 by Dr Charlotte Dravet, who has done much to reduce the uncertainty surrounding the disease. As Dr Dravet said at a conference last year:
“When the parents are well informed about the meaning of the genetics – that is to say this disease is not hereditary – they understand it is not their fault, but it is an accident they could not avoid, and most are relieved when they know the diagnosis and the cause of the disease.”1
We now know that Dravet syndrome typically results from mutations in the SCN1A gene, which affects the brain’s inhibitory neurons. These neurons use sodium channels to regulate electrical signals: in Dravet syndrome they malfunction, leading to frequent, intense seizures. The syndrome also causes a host of developmental, cognitive, and behavioural issues, and a heightened risk of premature death.
The management of Dravet syndrome is particularly challenging. Some antiseizure medications that are standard for other forms of epilepsy are not just ineffective in Dravet syndrome—they can worsen intellectual disabilities and developmental delays. For most affected infants, standard epilepsy surgeries are not indicated.2
Among indicated anti-seizure medications in Dravet syndrome, valproate is often first-line. However, one or more additional medications—such as clobazam, stiripentol, or cannabidiol—are usually needed to control seizures. Other, newer therapies have also been approved in specific combinations and/or for specific age groups. Non-pharmaceutical interventions include vagal nerve stimulation and ketogenic diets. However, even with multiple medications or interventions seizures may continue, and affected children will often need complex, costly support throughout their lives.3,4
The potential impact of gene therapy
Genic procedures and therapies offer hope for profound change. Correcting the underlying SCN1A mutations could halt the disease in its tracks and maybe even provide a cure. So far, there have been promising preclinical results and a handful of products are being trialled in humans.
But the prospect of gene therapy in Dravet syndrome also brings new challenges. The first is that, for the best possible outcomes, it would require early and decisive intervention in very young patients. As Dr Dravet said last year:
“To obtain results not only on the seizures but also on the impairment of the development, this type of treatment should be started at the beginning of the disease as soon as the diagnosis has been confirmed. Thus, it will be necessary to quickly decide to treat the little patient only with ASM [antiseizure medication] or with a genic procedure, probably not later than during the second year.”1
Such a decision could be daunting. Partly because Dravet syndrome is difficult to diagnose without specialist experience – and such expertise is as rare as the disease itself. But there are other issues associated with treating this young and potentially vulnerable patient group.
For example, gene therapy itself can carry significant risks. Administration routes such as intracerebroventricular (via the skull) and intrathecal (via the spinal column) may allow therapies to bypass the blood-brain barrier and reach the millions of neurons needing treatment. But these techniques can also cause potentially severe complications, including infections and intracranial bleeding. Furthermore, gene therapies may require significant periods of immunosuppression, which reduce the risks of a life-threatening immune response but add to the risk of infection.
New uncertainties
Not all cases of Dravet syndrome are the same. Dozens of specific mutations in SCN1A can cause the disease. Indeed, some types of the syndrome are not linked to SCN1A mutations all, raising questions about whether gene therapy would work for everyone with the disease. Understanding different genetic profiles has already helped in the development of treatments, but further research is needed.
Equally, not all gene therapies are—or will be—the same. For example, instead of repairing the defective copy of SCN1A, another approach would be to use gene therapy to boost the protein productivity of the non-defective copy. There may also be differences in how the therapy is delivered at a cellular level. Gene therapies are commonly delivered into cells using viral vectors. However, SCN1A may be too large a gene for the conventional approach, and so dual-viral vector techniques are being investigated, as are other types of vector entirely such as lipid nanoparticles.
It is currently unknown how these different approaches might impact the effectiveness and safety of gene therapy in Dravet syndrome. Or if different approaches will be needed for different patients. What we do know is that the cost and logistical burden of gene therapy is high and so, even once the risk:benefit profile is established, this treatment option may not be available to all patients.
Back to the here-and-nowDespite these uncertainties, the leaps in scientific understanding that have been made already are extraordinary, and it is probable that many challenges will be solved or mitigated in the coming decades. In scientific terms, that’s not long. But for many patients and their families, it will be too late. In the short-term, they will need the support of multidisciplinary medical teams and access to the most appropriate and effective combinations of antiseizure medications. Even before gene therapy becomes available, there is much work that can be done to support such families.
The TVF team work to raise awareness across a number of rare, neurological and neurodegenerative disorders. If you would like more information on our work in this area please contact enquiries@tvfcommunications.co.uk.
By Stephanie Maury
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