About Myotonic Dystrophy Type 1 (DM1)
Myotonic dystrophy is an inherited condition broadly characterized by progressive muscle weakness and myotonia (when muscles are unable to relax following contraction), central nervous system defects, cardiac issues, and endocrine dysfunction. It is a clinically and genetically heterogeneous disease with two distinct forms: myotonic dystrophy type 1 (DM1) due to mutations in the DMPK gene and the milder, more recently recognized myotonic dystrophy type 2 (DM2) due to mutations in the CNBP gene.
DM1 can be further subdivided into sub-categories that vary in terms of age of onset, predominating symptoms, and symptom severity (De Antonio et al, Rev. Neurol. 2016). The classical form of DM1 presents in the third decade of life with muscle weakness, delayed muscle relaxation (myotonia), cataracts, cardiac conduction abnormalities, and daytime sleepiness. In contrast, earlier onset forms including congenital, infantile, and juvenile DM1 are associated with poor muscle tone, respiratory insufficiency, intellectual disability, and behavioral disturbances, among other symptoms. Finally, as the name suggests, mild DM1 presents later in life with fewer and less severe symptoms.
DM1 is the most common form muscular dystrophy that affects adults. It is estimated to affect 1 in 8,000 individuals worldwide and up to 40,000 people in the U.S. (Myotonic.org).
For the majority of patients with DM1, lifespan is substantially reduced, with respiratory failure and cardiac disease accounting for the majority of patient deaths. For congenital DM1 patients, there is a 25% chance of mortality in the first 18 months of life and only a 50% chance of survival into the mid-30s. Meanwhile, the classic and mild forms have an average lifespan of 55 and 64, respectively (Reardon, Arch Dis Child, 1993, Mathieu, Neurology, 1999).
In addition to increased mortality, there are many other debilitating features of DM1 that impact patient quality of life. The invariable development of muscle weakness and myotonia leads to difficulty performing basic tasks, an inability to hold the head in place (“head drop”), facial muscle weakness resulting in a distinct, abnormal facial appearance, and the loss of independent ambulation. Muscle weakness also impacts other functions, including the ability to swallow and breathe, which together may account for some cases of respiratory distress seen in later stages of disease. Difficulty breathing specifically during sleep, also termed Obstructive Sleep Apnea (OSA), can lead to excessive daytime sleepiness and lost productivity. Disturbances in the central nervous system cause profound fatigue (90.8% patients), hypersomnia (87.9% of patients), and various cognitive challenges (>50% of patients). At later stages of disease, neurofibrillary tangles and pathologic tau protein aggregates are present in DM1 brain. Finally, endocrine dysfunction can lead to insulin resistance and infertility, particularly in men. (Heatwole, Neurology 2012, Meola & Cardani, Biochimica et Biophysica Acta, 2015).
Children impacted by either congenital or juvenile forms can have additional complications. At least 40% of children and young adults experience fecal incontinence and other gastrointestinal disturbances that are reportedly the most troublesome symptom of their disease for some individuals. Furthermore, the majority of congenital and juvenile DM1 patients experience some degree of intellectual disability, while up to 50% of these children have a concomitant psychiatric disorder, such as depression, anxiety, ADHD, or autism spectrum disorder (Johnson et al, Neurology, 2016).
Common DM1 Symptoms
DM1 results from a mutation in the DMPK gene. The DMPK gene provides instructions for making a protein called myotonic dystrophy protein kinase, whose specific function is not completely understood. One region of the DMPK gene contains a segment of three DNA building blocks (nucleotides) that is repeated multiple times. This sequence, cytosine-thymine-guanine (CTG), is called a triplet or trinucleotide repeat. In most people, the number of CTG repeats in this gene ranges from 5 to 38, while patients with DM1 have a longer repeat tract. The expanded repeat tract is unstable and can undergo further expansion and contraction throughout the lifetime of a DM1 patient, with a bias towards expansion. Therefore, the length of the CTG repeat tract differs across cells of a patient, and across individuals with the disease. Tissues with non-dividing cells such as skeletal muscle can harbor repeats that are thousands of bases in length, even when the same repeat tract as measured in blood is only hundreds of bases in length (Thornton et al, Ann Neurology, 1994). Longer CTG repeats correlate with earlier age of onset and greater disease severity (Harley et al, Am J Hum Gen, 1993). Furthermore, the repeat length can expand across generations of a family. This phenomenon, called anticipation, also occurs in other expansion repeat diseases and results in younger generations being more severely affected. In fact, many parents are not aware that they carry the expansion mutation until they have a child that is born with congenital DM1. The mutation is inherited in an autosomal dominant fashion, meaning there is a 50% chance a child of an affected parent will also have the DM1 expansion.
The Role of Toxic CUG Repeats in Disease Pathogenesis
Multiple biological pathways are activated as a result of the CTG repeat expansion, but the most well-established pathway is the sequestration, or “sponging”, of other proteins in the cell by the RNA produced from mutant DMPK. When DMPK containing expanded CTG repeats is copied into RNA, the RNA forms abnormal structures containing extremely long CUG repeats. This RNA binds to and sequesters members of the Muscleblind-like family of RNA binding proteins (MB), causing both loss of MB function and retention of the expanded DMPK RNA in the nucleus (Miller et al, EMBO 2000). Under normal conditions, MB regulates the proper splicing of RNAs encoding proteins critical for skeletal muscle, cardiac, and nervous cell function (Pascual et al, Differentiation, 2006). Loss of function of this protein contributes substantially to the diverse array of neurologic, muscular, and cardiac abnormalities seen in this disorder (Kanadia et al, Science 2003, Charizanis et al, Neuron 2012, Poulos et al, HMG 2013) and it has been shown in mouse models of DM1 that restoration of MB function reverses DM1-related deficits (Kanadia et al, PNAS 2006).
Small Molecule Design Approach
Expansion’s approach to treating DM1 is focused on identifying and lead optimizing novel small molecule drugs that can bind the CUG repeat specifically and potently and free MB protein so it can go on to do its normal job of regulating pre-messenger RNA splicing.
CUG repeats form an extensive, repetitive array of binding sites favored by MB protein.
Expansion small molecules (pictured in orange) are designed to bind toxic CUG repeats and free MB.
Expansion has used its platform of enabling technologies to demonstrate that its small molecule compounds are capable of binding disease causing toxic CUG repeats but not healthy non-disease repeats. This is important validation as it shows compounds can be engineered to bind with limited off-targets. Selectivity appears to be driven by structure as opposed to sequence, as shorter CUG repeats do not form the toxic secondary structure present in DM1, and are not targeted by our compounds. In addition, Expansion recently published findings in Nature Chemical Biology examining its small molecule dimeric compounds that are active and selective in various assays of DM1.
Binding affinity (Kd)
ACS Chem. Biol. 2013, 8, 2312−2321. dx.doi.org/10.1021/cb400265y
In Vitro Splicing Rescue (%)
DM1 Patient Fibroblasts
In Vivo Splicing Rescue (%)
DM1 Mice Over 14 Days
Binding to Healthy Fibroblasts (CUG15)
Binding to DM1 Fibroblasts (CUG500)
Binding to DM1 Fibroblasts (CUG500)
Improvement of Pre-mRNA Splicing Defects
Given the complexity of DM1 and the diverse interventions available (or not available), patients must coordinate care between many different specialists and augment their lives to meet these needs. It is no surprise that this puts an incredible burden on patients and their families. It is also extremely uncommon to find families with only one family member affected by DM1; given the autosomal dominant inheritance pattern, in most cases, multiple individuals in multiple generations of a family are affected. A cost of illness study published in 2013 estimated the cost to each affected American individual to be $32,236 per year, which includes medical costs, non-medical costs associated with lifestyle modifications (i.e. adapting homes and cars), and income loss (MDA.org). This translated into an annual national cost of $448 million based on an estimated prevalence of roughly 14,000. Given that the current U.S. prevalence is more than twice that quoted in this analysis, the reported annual national cost is likely a gross underestimation of the true value.
To date, there is no disease-modifying therapy that exists for DM1. The lack of targeted interventions and the resulting reliance on symptomatic management is responsible for the substantial financial burden, morbidity, and mortality associated with this disease. The ability to even partially alleviate some of these deficits would greatly improve quality of life for patients and their families.