A significant unmet medical need remains in DMD due to inadequate dystrophin production in critical organs and tissues. Sufficient production of dystrophin and restoration of muscle integrity can likely only be achieved through adequate intracellular target engagement in the skeletal muscle, heart and diaphragm.
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene for dystrophin, a protein essential for the normal function of muscle cells (myocytes). In healthy individuals, the dystrophin protein plays a key role in strengthening and protecting myocytes during activity as muscles contract and relax. In patients with DMD, little or no dystrophin is produced as a result of genetic mutations that lead to certain exons in the dystrophin gene being misread. Without dystrophin, myocytes are damaged, and, over time, this results in progressive loss of muscle function throughout the body.
DMD primarily affects boys and young men, with an estimated prevalence of 10,000 to 15,000 people in the United States, and a similar prevalence in the European Union.
In patients with DMD, progressive muscle weakness occurs throughout the body.
Early in childhood the large, proximal (close to body core) skeletal muscles are affected and later the distal muscles. The lower body muscles are affected earlier than the upper body muscles. Patients may have difficulty standing, climbing stairs and maintaining balance. Patients may ultimately become dependent upon a wheelchair.
In the later stages of the disease, the heart and diaphragm are affected, and this ultimately contributes to morbidity and mortality.
An ideal treatment would not only be effective in restoring high amounts of dystrophin in the skeletal muscles, but also in the heart and diaphragm given they are key organs responsible for disease morbidity and mortality.
Entrada is developing oligonucleotides conjugated to our Endosomal Escape Vehicle (EEV™) platform for the treatment of patients with DMD.
The EEV platform promotes high cellular uptake and highly efficient endosomal escape, resulting in a substantial amount of the oligonucleotides reaching pre-mRNA in the nucleus. Our proprietary oligonucleotides promote enhanced exon skipping, restoration of the reading frame and dystrophin protein production. In preclinical models, we have observed that conjugation of an oligonucleotide to our EEV results in multi-fold greater exon skipping and dystrophin protein production than the oligonucleotide alone, with near complete correction of dystrophin in certain tissues.
Differentiation of EEV-Oligonucleotides
Limited exposure in target tissues and poor endosomal escape have been the two biggest barriers to achieving greater dystrophin levels with oligonucleotide therapies. Because of the unique mechanism of action of the EEV platform and the broad biodistribution of our oligonucleotide conjugates, we see not only significant dystrophin production in the muscles like the heart but also uniform dystrophin production beyond the vasculature within tissues. Given cardiomyopathy is a leading cause of death for patients with DMD, we believe this increased level and higher myocyte distribution of dystrophin observed preclinically may potentially translate to improved cardiac function in patients with DMD.