Anti-sense oligonucleotide platform for rare genetic diseases of the nervous system - Project Summary:
Antisense oligonucleotide platform for rare genetic diseases of the nervous system
Rare diseases affect nearly one in ten people in the United States. Approximately two million of
those individuals suffer from rare diseases of the nervous system such as ALS, Fragile X
Syndrome, Rett Syndrome, and severe epileptic encephalopathies. Orphan disease variants are
often not of interest to large pharmaceutical companies. As a result, hundreds of thousands of
patients are left not knowing the cause, potential treatments, or prognosis for their disease
creating a large unmet medical need globally.
Antisense oligonucleotides or ASOs have several characteristics that make them amenable to a
precision medicine approach for treating underlying genetic defects. The FDA has recently
approved multiple ASO products for the treatment of rare genetic disease in severe cases
unresponsive to traditional drug therapies. These include nusinersen for the treatment of spinal
muscular atrophy, eteplirsen for the treatment of Duchene muscular dystrophy and mipomersen
for the treatment of homozygous familial hypercholesterolemia. Therapeutic ASOs are generally
15-30 nucleotides in length and complementary to mRNA or pre-spliced mRNA to either inhibit
translation through RNAseH mediated mRNA decay or induce exon skipping or inclusion during
mRNA splicing. The type of disease-causing variant, whether recessive, dominant gain-of-
function or dominant loss-of- function (haploinsufficiency) and intended mode of action of the ASO
dictate the design requirement for ASO treatment.
Despite the recent clinical successes, ASO design is not rational and requires hundreds of ASO
candidates to be synthesized and then evaluated in cell-based assays to identify top ASO
candidates. Many of these ASOs often contain undesirable characteristics reducing the probability
of positive outcomes in in vivo models and in safety evaluation.
In Phase 1, we propose to construct a variant classification algorithm to determine which variants
may be amenable to ASO treatment and construct an algorithm to design an appropriate ASO
therapy for the associated rare disease variant. We will use ASOs designed through these
algorithms to test their efficacies in patient derived iPS cell-derived neurons with causative
variants for early-infantile epileptic encephalopathy, a devastating neurological disease
associated with rare variants in KCNQ2 and KCNT1, often resulting in significant intellectual
development impairment and mortality in childhood. We will expand our ASO platform to new
genetic diseases and ASO methodologies in Phase 2 with the goal of developing treatments for
patients with rare neurological disorders.
