An antisense oligonucleotide therapy for KCNT1 based epileptic encephalopathies - Project Summary:
Malignant Migrating Partial Seizures of Infancy (MMPSI) is a severe epileptic encephalopathy
(EE) resulting in intractable seizures and severe developmental delays. It manifests early in
childhood and can have devastating impacts on affected individuals and their families. Mutations
in a gene called KCNT1 have been associated with MMPSI. KCNT1 encodes an ion channel,
highly expressed in the nervous system, that regulates neuronal excitability. Current therapies for
KCNT1-based MMPSI include a variety of anti-epileptic drugs with limited efficacies in the clinic.
More importantly, these drugs do not target the underlying genetic cause of the disease.
Antisense oligonucleotide (ASO) therapies may, however, provide a novel therapeutic strategy
for targeting mutant KCNT1 channels expressed in this disorder. Recent clinical demonstrations
of ASO efficacy in other genetic diseases, such as spinal muscular atrophy and muscular
dystrophy, have validated this approach and given hope to patients. ASOs are short, synthetic
stretches of modified genetic material that can be designed to recognize and knockdown specific
gene products. ASO drugs are administered directly into the central nervous system by injection
into the fluid surrounding the spinal cord. In this research program, ASOs will be designed and
tested in human cell-based models of KCNT1-linked EEs with the goal of knocking down KCNT1
gene products, including those containing the malignant mutation. ASOs will be designed to
assess targeting of many regions of the KCNT1 gene which would enable evaluation of gene
knockdown independent of the location of the mutation. Disease models have been previously
characterized by electrophysiological screening and include patient-derived neuronal cells, as
well as control cell lines that have been genetically-engineered to express mutant KCNT1. In a
subsequent phase of the research program, the final candidate ASOs from this phase will be
further optimized in in vivo models and ultimately developed as therapies for KCNT1-based EEs.
Ultimately, the proposed research stands to benefit this specific population of patients with KCNT1
mutations, who suffer from devastating seizures and neurological deficits, as well as provide
additional traction for the development of other ASO-based therapies for severe genetic diseases.
