Abstract Details

Title Optimization of AOC-1001, an antibody-oligonucleotide conjugate targeting the underlying cause of myotonic dystrophy type 1

Topic Movement Disorders

Presentation(s) Emerging Science Session (3:45 PM-3:49 PM)

Poster/Presentation
Number 011

Background

The toxic gain-of-function DMPK mRNA can be targeted with oligonucleotides for degradation. Delivery of oligonucleotides into muscle has been limited. Antibody-Oligonucleotide Conjugates (AOCs) represents a new class of therapeutics allowing delivery of oligonucleotides to target tissues.

Objective

To develop therapy for Myotonic Dystrophy Type 1 (DM1), a rare, progressive neuromuscular disease with no approved therapy, that arises from CTG repeat expansions in the DMPK gene.

Design/Methods

We conducted biochemical and cell-based studies with the lead DMPK siRNA, as well as pharmacological evaluation of the clinical candidate AOC1001 in non-human primates.

Results

Cell fractionation of DM1 patient-derived cells treated with siDMPK.19 demonstrated a reduction of DMPK mRNA levels in nucleus (60%) and cytoplasm (80%). Immunofluorescent analysis showed reduction of DM1-associated nuclear foci by 50% in the myotubes cultured from DM1 patients treated with siDMPK.19. Treatment with siDMPK.19 corrected the aberrant splicing (56.5% correction of splicing signature) in myotubes obtained from DM1 patient. In vivo experiments in non-human primates demonstrated excellent activity of DMPK-targeted AOC1001, composed of monoclonal antibody targeting transferrin receptor (TFRC) and DMPK siRNA, in muscle. A single intravenous (IV) infusion of AOC1001 at 0.6, 2, or 6 mg/kg (siRNA dose) produced a dose-dependent reduction in DMPK expression in the quadriceps, gastrocnemius, and tibialis anterior muscles with an ED₅₀ < 1 mg/kg. Following a single IV dose of AOC1001 at 2 mg/kg (siRNA dose), the approximately 75% reduction in DMPK mRNA levels was sustained up to three months post-dose in quadriceps and gastrocnemius. Four weeks after a single IV administration of AOC1001 at 6 mg/kg (siRNA dose), substantial reduction (about 75% or more) of DMPK mRNA was observed in heart and in a large variety of skeletal muscle assessed, including the intercostals and diaphragm.

Conclusions

Based on these data, clinical investigation of AOC1001 in DM1 patients is planned.

Authors/Disclosures
Barbora Malecova, PhD (Avidity Biosciences) PRESENTER	Dr. Malecova has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Malecova has received stock or an ownership interest from Avidity Biosciences.
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