FDA approves first gene therapy for treating Duchenne muscular dystrophy
Delandistrogene moxeparvovec was approved by the Food and Drug Administration (FDA) in June 2023 for the treatment of ambulatory patients ages 4-5 years with Duchenne muscular dystrophy (DMD) who have a confirmed mutation in the DMD gene and do not have a pre-existing medical reason preventing treatment with the therapy. Approval was granted via the accelerated approval pathway.
Delandistrogene moxeparvovec is a recombinant adeno-associated virus vector-based gene therapy designed to deliver a gene that leads to expression of a microdystrophin comprising key functional domains of the normal dystrophin protein. It is administered as a single intravenous dose.
The approval was based on analysis of results submitted to the FDA from randomized trials indicating that the microdystrophin was expressed in patients treated with the therapy. A clinically meaningful and statistically significant difference in North Star Ambulatory Assessment score was reported for patients treated with delandistrogene moxeparvovec compared with a propensity-score-weighted external control cohort after 1 year. Adverse effects noted in the trials included myocarditis, elevations of troponin-I, acute liver injury, and thrombocytopenia. Studies are ongoing to demonstrate clinical benefit.
Muscular dystrophies are a group of inherited diseases characterized by progressive muscle degeneration and weakness. They are caused by mutations in genes encoding muscle proteins. Over 40 causative genes have been identified.
Duchenne muscular dystrophy (DMD) is the most common and most rapidly progressive muscular dystrophy. It is an X-linked condition and so usually affects only boys. Most patients lose the ability to walk by 12 years of age and require ventilatory support by 20 years of age.
Diagnosis of DMD is often delayed. Signs that indicate possible DMD include: delayed motor milestones, frequent falls, abnormal gait, muscle pain, calf hypertrophy, speech and language delay, and difficulty with jumping, running, climbing steps, and rising from the floor. Creatine kinase levels are elevated. Diagnosis is confirmed by genetic testing.
Multidisciplinary care for patients with DMD is focused on prolonging function, symptom management, and maintaining a good quality of life for as long as possible. Survival has been improved by the use of noninvasive respiratory support and cardioprotective drugs. Severe scoliosis and the need for corrective surgery can be avoided, and the need for mechanical ventilation delayed, by early and aggressive use of corticosteroids.
With few exceptions, all generalized muscle dystrophies can be managed using the principles for managing DMD. This is also the case for spinal muscular atrophy (SMA), an inherited motor neuronopathy with symptoms similar to those of the muscular dystrophies. Drugs for treating SMA are now available in clinical practice.
Muscular dystrophies are progressive, generalized diseases of muscle, most often caused by defective or specifically absent glycoproteins (e.g., dystrophin) in the muscle membrane. All muscular dystrophies are characterized by ongoing degeneration and regeneration of muscle fibers. The most common and rapidly progressive muscular dystrophy is the X-linked Duchenne muscular dystrophy (DMD), which is diagnosed by testing for DMD gene deletion or duplication. Becker muscular dystrophy is related to DMD but is less severe. Other muscular dystrophies include myotonic dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies, and congenital muscular dystrophies. This topic will focus mainly on DMD, with some discussion of other muscular dystrophies and of the related condition spinal muscular atrophy.
History and exam
Key diagnostic factors
- family history of DMD
- male sex
- imbalance of lower limb strength
- lower extremity musculotendinous contractures
- delayed motor milestones
- calf hypertrophy
- ambulation difficulty and falls
- diminished muscle tone and deep tendon reflexes
- normal sensation
- Gowers sign
Other diagnostic factors
- toe walking
- urinary and bowel incontinence
- mild to severe intellectual disability
- family history
- male sex
1st investigations to order
- serum creatine kinase (CK)
- genetic testing
Investigations to consider
- electromyogram (EMG)
- muscle biopsy
- muscle MRI
DMD: ambulatory stage
DMD: early nonambulatory stage
DMD: late nonambulatory stage
spinal muscular atrophy (SMA)
- Static encephalopathies (cerebral palsy)
- Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management
- Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management
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