By Dulara Janani Kuruppu
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy (a group of neuromuscular diseases that cause the degeneration of skeletal muscles) and is fatal to its sufferers, who are unlikely to survive beyond their early thirties. Its symptoms arise early in patients, commonly between the ages 2 and 4, and include restricted mobility, a waddling gait and muscle atrophy (a reduction in muscle mass).
The life expectancy of affected patients, who are mostly boys, has been increasing over the years, and researchers have been striving to discover a complete cure for this debilitating genetic disorder. At last, it appears that they may have found one: the possibility of implementing gene therapy to treat patients with DMD has become a compelling prospect in recent years.
The effects of DMD on muscle tissue
The Inheritance of Duchenne Muscular Dystrophy
The gene that codes for the synthesis of a protein called dystrophin is located on the short arm of the X chromosome. The mutated form of this gene prevents the production of functional dystrophin, which leads to the symptoms of DMD. Dystrophin is a crucial protein that facilitates efficient muscular contraction. It does this by linking actin filaments in myofibrils in skeletal muscle tissue to membrane proteins.
DMD develops almost exclusively in boys, due to the recessive sex-linked allele which causes the degenerative disease. Females have two X chromosomes. For a female to be affected, she would have to inherit two mutated alleles for DMD from her parents, which is very unlikely. It is more probable that a female would be a carrier, who would inherit one mutated allele and one normal allele, which means that she is unaffected, but can pass the mutated allele to her offspring. Since males have only one X chromosome and a Y chromosome, it is not possible for a male carrier to exist. Instead, any male who inherits the mutated allele on the X chromosome, most likely from a carrier mother, will be affected with DMD. This is because there is no other X chromosome to mask the effects of the recessive allele that causes DMD.
Gene Therapy in Treating DMD
Gene therapy involves the alteration of a patient’s genetic makeup to improve or reduce the severity of a disease. Unlike more traditional methods of treatment, such as surgery or medication, gene therapy enables doctors to address the underlying cause of a patient’s condition. A vector is used to deliver the different gene to cells in the body. This vector is primarily a virus that is not capable of causing disease.
In 2015, a team of researchers from the University of Missouri announced their success in treating dogs with DMD using a microgene enclosed in a viral vector. This discovery was significant because until then, the DMD gene could only successfully be taken up by all muscles in the bodies of small rodents, such as mice. The researchers at the University of Missouri, however, used dogs as their size was similar to that of a young boy, whom DMD was most likely to affect. Since the gene for dystrophin is one of the largest in the human body and is not possible to be carried by minuscule virus particles, the researchers used a more compact form of the gene, a microgene. After a decade of administering the treatment, the treated dogs continued to lead normal lives with no adverse health effects, making this a promising prospect for further research.
In 2023, the U.S. Food and Drug Administration’s approval of Sarepta’s gene therapy scheme (Elevidys) for DMD marked a monumental shift in the progress of gene therapy research to treat this neuromuscular disease. Here, the microgene is transferred to the patient by an adeno-associated virus (AAV) vector through an IV infusion. The micro-dystrophin gene is taken up by cardiac and muscle cells which then produce dystrophin. However, the treatment is available only to a restricted group of patients aged four and five until enough evidence is observed of its efficacy and safety.
In the future, doctors and researchers hope to hone the technique of gene therapy to treat DMD, and that this treatment proves to be as effective in enhancing the lives of several affected children worldwide, extending lifespans and ensuring a better quality of life for its patients.
References
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