Biomarkers of Survival for Duchenne Muscular Dystrophy

Biomarkers are pivotal in the diagnosis, prognosis and treatment of fatal diseases, offering invaluable insights into patient outcomes. Survival biomarkers, in particular, guide personalized treatments and are crucial for rare diseases, which pose unique challenges in data collection and research reliability.

The development and validation of biomarkers is a complex process requiring rigorous scientific scrutiny, especially in the context of rare diseases where the low prevalence and variability in symptoms make universal applicability a challenge. Causaly can expedite this process by streamlining biomarker identification, enabling early drug discovery teams to transition discovery projects into clinical programs with confidence. In this use case, we explore potential survival biomarkers of Duchenne Muscular Dystrophy (DMD), a rare disease of the skeletal muscle.

Muscular dystrophies (MD) are a collection of rare progressive conditions which cause the breakdown of skeletal muscles. In 2022, the global prevalence of MD was estimated to be 3.6 people per 100,000.¹ The severity of MD escalates when vital organs, such as the heart and respiratory muscles, are affected.

Among the various types of MD, Duchenne Muscular Dystrophy (DMD) stands out as one of the most severe forms, affecting 1 in 3,500 male births worldwide.² DMD is an unforgiving disease that progresses rapidly, often necessitating the use of wheelchairs as early as the age of 10,³ with a median survival age of just 22 years.⁴

Like many rare disorders, DMD has a genetic basis, with roughly 80% of such conditions originating from genetic mutations.⁵ DMD follows this pattern, resulting from mutations in genes responsible for muscle activity. In most DMD patients, dystrophin, a crucial cytoskeletal protein, is mutated, leading to muscle degeneration and further complications.⁶

DMD is a fatal disease with no cure. Identifying biomarkers linked to DMD patient survival is vital for understanding disease progression, evaluating treatment effectiveness, and enhancing outcomes for those with this rare disease.

Approximately 500 potential biomarkers for DMD were identified using Causaly. Notably, this number is significantly fewer identified for multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) – an even rarer neuromuscular condition than DMD.⁷ With between 7000 to 8000 other rare diseases to contend with,⁸ this emphasizes the significant unmet need in DMD research.

Based on Causaly’s findings, the literature from 2018 to 2022 has reported approximately 30 potential biomarkers related to DMD survival, as shown in Figure 1. Dystrophin, which is heavily implicated in DMD pathogenesis, emerged as the biomarker with the most evidence. Interestingly, among the biomarkers studied in the past five years, FLT-1 (also known as VEGFR-1) demonstrated significant evidence, trailing closely behind dystrophin.

FLT-1 is a tyrosine receptor, predominantly expressed on vascular endothelial cells, which plays a key role in angiogenesis. It has gained attention as a potential biomarker and treatment target for DMD, a condition worsened by poor blood flow and inflammation.⁹

Recent studies also linked FLT-1 to increased longevity due to its protective effects against hypertension, heart disease and stroke.¹⁰ In DMD mouse models, the inhibition of FLT-1 can improve symptoms of DMD, demonstrating that FLT-1 is required in the perinatal stages of survival.¹¹ Similarly, FLT-1 antagonists have shown to promote angiogenesis and improve muscle pathology,¹² which impacts survival. Given its involvement in angiogenesis, inflammation and muscle repair, FLT-1 emerges as a promising survival biomarker for DMD.