Peptide and Oligonucleotide Therapeutics Group

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.

Spinal muscular atrophy 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 ASOs to correct SMN2 aberrant splicing and restore functional SMN protein.

Amyotrophic lateral sclerosis 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.  

Converging lines of evidence implicate alpha-synuclein in a causative role in PD and its progression and alpha-synuclein has been identified as the major protein component in Lewy bodies and Lewy neurites which are pathological hallmarks of PD. Reduction in the level of alpha-synuclein has been shown to provide significant therapeutic effect in pre-clinical models of PD.

In our approach, we are developing a novel class of brain-penetrating ASO targeting SCNA RNA to reduce alpha-synuclein protein expression in the brain following systemic administration. This diseases-modifying therapy has a significant translational potential.

A defining pathological feature of AD is intra-neuronal tau deposition as a result of aberrant level of phosphorylated tau (pTau). The protein phosphatase 2A (PP2A) is the dominant kinase responsible for tau phosphorylation. Our therapeutic strategy is to increase the relative amount of methylated PP2A by preventing demethylation of the protein. We are developing ASOs that knock down protein phosphatase methylesterase 1 (PME-1) which demethylates PP2A. Therefore, using antisense approach to promote the methylation event driving PP2A tau-phosphatase activity has therapeutic potential for AD.

Spinal bulbar muscular atrophy, commonly known as Kennedy’s disease (KD), is a slowly progressive rare neurodegenerative disease in which degeneration of lower motor neurons results in muscle weakness and fasciculation in affecting adult males. SBMA is caused by a genetic mutation (CAG repeat code for polyglutamine) of the androgen receptor gene. The polyglutamine-expanded AR (polyQ AR) forms oligomers and interfere with various cellular processes with deleterious effect.

In this project, we are developing ASO targeting polyQ AR to lower the level or AR. This therapeutic intervention provides a significant benefit by reducing the symptoms and slowing the disease progression.

Upregulation of autophagy as a means to promote clearance of protein aggregates and restore neuronal health holds great promise as a viable therapeutic approach for neurodegenerative diseases. As part of this research program, we are developing novel autophagy-inducing peptides which are highly selective and can penetrate cell and BBB to reach their neuronal target.

We have discovered a potent 15 amino acid long autophagy-inducing peptide (BCN4) derived from the evolutionarily conserved domain (ECD) of the protein Beclin-1, a known master regulator of autophagy. The BCN4 peptide showed a significant upregulation of autophagy in the CNS following systemic administration in a reporter mouse model of autophagy.

Currently, we are further optimising this peptide to enhance its pharmacokinetics and evaluating the therapeutic applicability of this novel peptide in relevant mouse model of neurodegenerative diseases.

One of the greatest challenges facing neurotherapeutics development and in particular biotherapeutic such as peptides and ASOs, is blood-brain barrier (BBB)-permeability and CNS bioavailability. In order to unlock the therapeutic potential of these biotherapeutics, they need to reach their neuronal targets in CNS. Therefore, an integral component of our research that is focused on therapeutic ASOs and peptides, is development of a peptide-based delivery platform for systemic CNS delivery of these novel biotherapeutics.