Emerging Therapies in DMD Flashcards
What is DMD?
Duchenne’s muscular dystrophy is a severe muscle wasting disease caused by mutations in the DMD gene which encodes for the dystrophin protein.
What is the pattern of symptom onset?
- Symptoms start at 2-3
- Diagnosis at 5-6
- Wheelchair bound at 12-13
- Death in twenties
What are the genetics of DMD?
Defective gene is on the X chromosome, mutation are mostly deletions (some duplications and SNV). Mostly out-of-frame deletions causing less than 5% of dystrophin to be produced.
What happens when dystrophin is lost?
Weakening of sarcolemma
Free radical damage
Functional ischaemia
Cytosolic calcium overload
Regeneration failure
What are the clinical features of DMD?
Proximal weakness -> delayed motor milestones, waddling gait, Gower’s sign, calf pseudohypertrophy
Increased CK and transaminases
Cardiomyopathy (main cause of death)
Respiratory failure
Poor bone health -> fractures, growth delay
Cognitive/behavioural issues
How is DMD assessed?
North star ambulatory assessment
6 minute walk test
How is DMD currently treated?
Glucocorticoids
Nutrition
Endocrine management
Bone health management -> x-ray, DEXA, vit D/calcium, bisphosphonates
Cardiac management -> ACE inhibitors, ECG, echo
Respiratory management -> spirometry, sleep study
How do steroids work for DMD?
MoA unknown -> decrease muscle breakdown and improve inflammation and metabolism
Slows decline in muscle strength - initiated at plateau phase
Oral administration
Improve motor function, pulmonary function, prolongs ambulation, improves orthopaedic outcomes, cardiac function and survival
What are the side effects of steroids?
Weight gain
Slow growth
Delayed puberty
Cushing’s
Acne
GI symptoms
Cataracts
Bone loss -> major issue as DMD already weakens bones and increases fracture risk
What is Vamorolone?
A steroid drug lacking a 11beta hydroxy-carbonyl group.
It is a mineralocorticoid antagonist, meaning bone health is less affected, and there is less insulin resistance and fewer CNS effects.
What is Givinostat?
A pan-histone deacetylase inhibitor.
Preclinical evidence shows it prevented contraction-coupled degradation, decreased inflammation and increased myofiber area in mdx mice.
Effects only seen after 36 weeks in clinical trial! Affects downstream effects of dystrophin lost so takes time for an effect to be seen.
Exon Skippers
Aim to restore reading frame to change from DMD to BMD-like dystrophin -> a shorter but functional protein.
Weekly s.c./i.v. admin of antisense oligonucleotides.
Mutation specific
Good safety profile but limited fraction reaches the muscle cells
Difficult to quantify dystrophin to understand how much is produced
Using siRNA to bind the exon skipper to a MAb against TfR helps the drug to reach intracellularly
Stop Codon Readthrough
Forces machinery to read through stop codon and prevent truncation
Only works in ~10% of patients
Initially approved by EMA but now revoked
Effect was not of relevant magnitude for patients
Gene Therapy
Uses a viral vector to deliver cDNA in aim to restore missing dystrophin
But entire gene too large for VV -> use mini and micro-dystrophins which only contain crucial domains
Risk of pre-existing Abs against VV and immunogenic responses to components
Delivered to muscle once in lifetime
Large steroid dose needed to counteract vector-associated inflammation
Satralizumab
Ab against IL-6R -> dysregulated IL-6 causes muscle atrophy and bone loss
Aims to improve bone mineral density and reduce fracture risk
