3. Precision medicine: aetiology-based preventive treatments and
in progress treatments
Moving towards the future that, for some conditions is already the
present, we step into
- preventive therapy
- antisense oligonucleotides treatment
- gene therapy
Let’s explore and revise where we are at with preventive therapies and
other innovative therapies acting of mRNAs and DNAs of mutated genes
thus have a true potential of curing the disorder and preventing the
occurrence of symptoms.
The best example for which there is a very good scientific basis is
represented by GVG a GABAergic drug, recommended as the first line
therapy for infantile spasms and/or focal seizures in the first year of
life (Chiron et al 1997; Elterman et al 2001). Patients with TSC are at
very high risk for developing infantile seizures including spasms and
focal seizures and about two thirds of them evolve into refractory
epilepsy (Curatolo et al 2018). Patients with TSC also are at high risk
for neurodevelopmental disorders whose severity is strongly related to
age at seizure onset and epilepsy severity (de Vries et al 2015;
O’Callaghan et al 2004). Early targeted interventions increase the
probability of seizure-freedom and may protect neurodevelopment (Jóźwiak
et al 2011). Indeed, the multicenter study named EPISTOP Trial,
demonstrated that treatment with GVG as soon as EEG recordings show the
occurrence of epileptiform activity delays the onset and the severity of
epilepsy (Kotulska et al 2021). Thus, by reducing the risk of having
infantile refractory seizures, physicians have the power of protecting
motor and cognitive development.
Prenatal treatment with maternal pyridoxine supplementation is another
example of preventive therapy in epilepsies since it has been
demonstrated to improve neurological outcome in newborns with pyridoxine
dependent epilepsy and antiquitin deficiency (Stockler et al 2010).
Antisense oligonucleotides (ASOs) are synthetic oligonucleotide or
oligonucleotide analogs that are designed to bind to the RNA in order to
modulate the function of the targeted RNA. ASOs represent a novel
therapeutic strategy to treat neurodegenerative diseases and seizures of
severe epileptic encephalopathies. The best example of this new
therapeutic strategy is represented, outside epilepsy, by the antisense
drug Nusinersen that has been approved for the treatment of spinal
muscular atrophy (SMA). Additional specific ASOs drugs are also
currently in development for the treatment of amyotrophic lateral
sclerosis, Huntington’s disease, and Alzheimer’s disease (Bennet et al
2019).
In epilepsies, it has been suggested that ASOs targeting theSCN1A channelopathy might improve not only seizure control, but
also impact the co-morbidities associated with DS (Wirrel and Nabbout,
in 2019). In a mouse model of DS, intra-cerebro-ventricular ASOs was
demonstrate to reduce the incidence of electrographic seizures and
sudden unexpected death in epilepsy (SUDEP) by increasing the expression
of productive Scn1a transcript in the mouse brain (Han et al 2020). ASO
treatment is in progress also in humans, indeed the recruitment process
for patients in two age groups (aged 13 to 18 years and 2 to 12 years of
age) has begun [https://dravetsyndromenews.com/; the MONARCH trial
(NCT04442295) Stoke Therapeutics]. The purpose of this clinical trial
is to assess the safety of single ascending dose of ASO/STK-001 in
children and adolescents with DS. Treatment with STK-001 is expected to
increase the level of productive SCN1A m RNA resulting in the elevated
expression of the sodium channel Nav1.1 protein and restore
physiological levels, which is reduced in patients with DS.
In mouse models of SCN8A encephalopathy with gain of function mutations
an ASO injection reduced SCN8A transcript and determined delayed seizure
onset and lethality (Lenk et al 2020). At the same time, a Scn1a+/−
haploinsufficient mouse model of DS was also successfully treated,
intra-cerebro-ventricular injections extended survival of Dravet
syndrome mice from 3 weeks to >5 months (Lenk et al 2020).
A cure is urgently needed for Lafora disease a teenage-onset devastating
progressive myoclonus epilepsy. Current treatment is very disappointing
including metformin (see previous section). Antisense oligonucleotide
(Gys1-ASO) targeting the mRNA in the brain was administered by
intra-cerebro-ventricular injection in the mouse model. Treatment
determined a reduction of Lafora body formation (Ahonen et al 2021). The
Gys1-ASO could be administered to patients via lumbar puncture thus
reach the brain and be effective in also in patients.
Ataluren is an available drug, at present prescribed in patients with
Duchenne muscular dystrophy (Morkous 2020), which suppresses premature
stop codons caused by nonsense gene mutations thus enabling full-length
protein. A current clinical trial reached its Phase 2 (randomized,
double-blind, placebo-controlled clinical trial, NCT02758626) in testing
the safety and efficacy on seizure types and frequency of the drug in DS
with nonsense mutation or cyclin-dependent kinase-like 5 (CDKL5)
deficiency, (https://clinicaltrials.gov/ct2/show/NCT02758626).
For more than 10 years, gene therapy for neurological diseases has
experienced intensive research development. Most trials are still in
pre-clinical phase 1 and 2. Delivery is the major issue for central
nervous system therapies in general, and particularly for gene therapy,
the blood brain barrier restricts the passage of vectors thus strategies
to bypass this obstacle are a central focus of research. Gene therapy
products can be tailored to solve the pathophysiological mechanisms,
including the use of gene replacement, gene silencing, transplicing,
modulation of cellular pathways to improve phenotype or expression of
suicide gene (Piguet et al 2021). There are only few gene therapies
approved for the management of neurological disorders including two for
SMA (Zolgensma- Novartis and Spinraza- Biogen) (Servais et al 2021).
For epilepsy the gene therapy approach is still very much a challenge.
NPY is a neuropeptide expressed in the brain, where it acts as a
neuromodulator, affecting pathways that range from cellular to circuit
level. In the context of epilepsy, NPY is thought to act as an
endogenous anticonvulsant, indeed its overexpression in the brain with
the aid of viral vectors can suppress seizures in animal models of
epilepsy. Therefore, NPY-based gene therapy may represent a novel
approach for the treatment of patients with epilepsies (Cattaneo et al
2021). Wickham et al in 2019 demonstrate that NPY application, in
hippocampal slices surgically resected from patients with drug-resistant
TLE, significantly reduces chemically induced epileptiform activity in
the dentate gyrus (Wickham et al 2019). Increasing the levels of NPY
could be an alternative approach to achieve a therapeutic effect and
suppress seizure activity.
Gene therapy has delivered promising results in animal experimental
models raising the hopes that it might soon become available for
patients. CRISPR/Cas9 biotechnology holds great promise in neurological
therapy, pending the clearance of major delivery, efficiency, and
specificity hurdles (Gumusgoz et al 2021).
Table 3, here below, summarizes the above reported evidences