My group’s research focuses on improving and designing new therapies for motor neuron disease spinal muscular atrophy (SMA) and muscular dystrophies Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). These disorders are treatable with antisense oligonucleotides (ASOs) to correct the dysfunctional mRNA. The team focuses on the targeted delivery of these therapies using a peptide and antibody delivery vehicles towards skeletal muscle and central nervous system tissues. We work with academic and industrial collaborators to advance this work to early clinical development.
Cell penetrating peptides (CPPs) are short cationic or amphipathic peptides that actively and passively penetrate the cell membrane for effective intracellular drug delivery. These CPP-ASO conjugates transport ASOs into skeletal muscle, heart, brain and spinal cord; tissues which are otherwise impenetrable without invasive local administrations. The most recent designs are focused on (1) increasing safety and tolerability and (2) directing a more tissue specific uptake to reduce off target effects.
Antibodies are naturally occurring proteins capable of specific binding to target cell surface proteins and receptors. Antibodies are flexible drug carriers that can be directly conjugated to multiple chemistries of ASOs as well as siRNA and genome editing elements. We have investigated an antibody-ASO capable of enhanced uptake and activity in the brain and spinal cord over other brain shuttling vehicles. Importantly, Antibody-ASOs redirected ASOs away from the kidney, a major tissue associated with ASO accumulation and toxicity. We are currently working to expand this program with newly engineered antibodies.
Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice.
Ahlskog N. et al, (2020), Gene Ther
Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment.
Betts CA. et al, (2019), Hum Mol Genet, 28, 396 - 406
Evaluation of Cell-Penetrating Peptide Delivery of Antisense Oligonucleotides for Therapeutic Efficacy in Spinal Muscular Atrophy.
Hammond SM. et al, (2019), Methods Mol Biol, 2036, 221 - 236
Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment.
Gait MJ. et al, (2018), Nucleic Acid Ther
Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.
Walter LM. et al, (2018), EBioMedicine, 31, 226 - 242