Muscle Atrophy

Muscle atrophy is the loss of skeletal muscle mass that leads to muscle weakness and physical disability for patients. It is caused by a range of conditions spanning from rare genetic muscle diseases to common disorders like muscle wasting disease or cachexia.

Muscle atrophy is caused by a change in the balance between protein breakdown and protein synthesis signals. Muscle atrophy can be associated with the activation of pro-inflammatory cytokine pathways which induce protein degradation or inhibit growth factor pathways that promote protein synthesis. Genetic profiling of atrophic muscles has identified a group of ubiquitin ligases (E3 ligases) that are upregulated when muscle atrophy begins. Muscle-specific E3 ligase muscle RING finger protein 1 (MuRF1) has been shown to be upregulated in muscle atrophy. Genetic ablation of MuRF1 in mice has been shown by third parties to render muscles partially resistant to various conditions of muscle atrophy. MuRF1 is a difficult target to address with traditional approaches like small molecules because of the gene family of E3 ligases, however, it may be able to benefit from the specificity of treatment achieved with an siRNA.

Our AOC for muscle atrophy is made up of our mAb targeting TfR1 and an oligonucleotide targeting MuRF1, and is designed to employ both the catabolic and anabolic pathways associated with the degradation of protein in muscle cells.

We are focused on preclinical studies and identifying a muscle atrophy indication best suited for AOCs.

Pompe Disease

Pompe disease is a rare, autosomal recessive lysosomal storage disease that results in the toxic buildup of glycogen in the body’s cells, causing impairment of normal tissue and organ function. People with the infantile-onset form of the condition are most severely affected, suffering from progressive muscle weakness, respiratory deficiency, and heart problems. A late-onset form of Pompe disease can manifest in older patients and is generally associated with progressive weakness of the proximal muscles and varying degrees of respiratory weakness.

We are developing an AOC targeting the glycogen synthase 1 (GYS1) mRNA to diminish the toxic accumulation of glycogen in muscle. Reducing GSY1 in muscle will reduce the toxic accumulation of glycogen—our approach may be complementary to enzyme replacement therapy, which is how Pompe disease is currently treated. Preclinical studies are ongoing.

Immune Cells, Cardiac Tissues and Other Cell Types

We also intend to pursue the development of AOCs in cell types in addition to muscle to continue to add to our expanding pipeline. For example, in the field of immunology, we believe AOCs have the potential to target a broader set of cell types and diseases than traditional oligonucleotide therapies. We believe oligonucleotide therapies have the potential to address the challenges of immune responses at the RNA level; however, the ability to modulate immune responses has been hampered by delivery of these agents to immune cells. By identifying and optimizing antibodies for specific immune cell types, our goal is to leverage our AOC platform to develop product candidates that can deliver siRNAs to disease-driving subsets of immune cells. We are collaborating with Eli Lilly and Company initially on 6 mRNA targets in immunology and other select indications outside of muscle for the delivery, development and commercialization of AOCs.

Beyond immune cells, we are investing in our AOC platform to explore the full potential of our AOCs in cardiomyopathies, and diseases of cells and tissues inaccessible to other oligonucleotide technologies. We also have a collaboration with MyoKardia, a wholly-owned subsidiary of Bristol Myers Squibb, that will help us expand our therapeutic activities to include cardiac-specific indications.

Through internal discovery efforts and partnerships, our goal is to discover, develop and commercialize novel AOC therapeutics that overcome current barriers to the delivery of oligonucleotides and unlock their potential to treat a wide range of serious diseases currently lacking adequate treatment options.