Isaac Marks, Scientist at Avidity Biosciences explored how targeted delivery of oligonucleotides can be used to treat rare musculoskeletal disorders.  Avidity has developed an antibody-oligonucleotide conjugate (AOC) platform.
Marks commented: “Our AOC platform technology is a unique class of ADCs that combines the exquisite specificity and high affinity of monoclonal antibodies with an oligonucleotide cargo that precisely targets the genetic source of the disease.”
He continued to explain that this novel technology allows scientists to target new tissue types beyond the liver and deploy the appropriate type of oligonucleotide for different disease types.
The platform relies on using covalent linkers to link the oligonucleotide of choice to the antibody. Then, by selecting a siRNA or phosphorodiamidate Morpholino oligomer (PMO) Marks and his team could apply modification patterns to enhance resistance to enzymatic degradation.
Although this holds promise, oligonucleotides present a complex set of challenges. Marks stated: “All of the nucleotides themselves have limited cell uptake due to their large size and hydrophilicity, and when untargeted, they exhibit rapid renal clearance and poor biodistribution to target tissue types.” This points to some of the challenges scientists in the oligonucleotide therapeutics field.
Avidity has several candidates for muscular dystrophy in their clinical pipeline including Del-brax and Del-zota but Marks decided to focus on Del-desiran, a candidate in the Phase III trial for myotonic dystrophy (DM1). The drug works by targeting mutant DMPK mRNA to improve muscle function.
Results from this trial shed light on some important findings. Del-desiran resulted in improvements in myotonia symptoms. Video hand opening time (vHOT) showed that patients receiving the drug could open their hands quickly.
Marks added: “Though in those videos it is possible to quantitatively assess the improvement of the vHOT experienced by the patient receiving a 4 milligramme per kilogramme dose of Del-desiran.”
The advancements in AOC technology mark a pivotal moment in oligonucleotide therapeutics, expanding applications beyond hepatic targets to skeletal and cardiac muscles.