Antisense Therapeutic Laboratory

The focus of our research is to exploit antisense technology for the development of therapeutics for neurodegenerative diseases.

Our current aims are the development of gene-specific antisense therapy for spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). These are diseases of motor neuron degeneration in the brain and spinal cord leading to paralysis of voluntary muscles and death by respiratory failure. While SMA primarily affects infants and children, the average age of onset for ALS is around 55.

SMA is caused by deletion of the survival motor neuron 1 (SMN1) gene that results in a deficiency of survival motor neuron (SMN) protein in the spinal motor neurons leading to their selective loss. Humans have a second, nearly identical copy of this gene, SMN2. In the absence of SMN1, SMN2 cannot protect from disease development. This is due to a C-to-T mutation within exon-7 that leads to the exclusion of exon-7 in the majority (>90%) of SMN2 transcripts. This, in turn, leads to the production of a truncated, unstable SMN protein that is rapidly degraded. The remaining SMN2 transcripts that produce full-length functional SMN protein are insufficient to compensate for the loss of SMN1. We have been using antisense oligonucleotides (ASO) to correct SMN2 aberrant splicing and restore functional SMN protein.

ALS is a fatal neuronal disorder that is caused by the progressive dysfunction and death of motor neurons in the brain and spinal cord. The majority of ALS cases are sporadic (90%) with the remaining 5-10% being familial. Mutations in a variety of genes have been implicated in familial ALS. The RNAs from these genes and their protein products have been shown to cause motor neuron toxicity and death. Currently, we are developing ASOs tailored towards some of the most common ALS-causing genes such chromosome 9 open reading frame 72 (C9orf72), superoxide dismutase 1 (SOD1) and ataxin-2.  

In order to unlock the therapeutic potential of the ASOs for these devastating lethal diseases, they need to reach their neuronal targets in the central nervous system (CNS). Therefore, an integral component of our research that is focused on ASOs will also be development of a peptide-based delivery platform for systemic CNS delivery of these novel biotherapeutics.

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