Avidity Biosciences: Explaining a complex mechanism of action
Avidity Biosciences is working on a cure for several inherited muscle dystrophy diseases, including Duchenne muscular dystrophy and myotonic dystrophy.
These conditions are associated with severe symptoms – muscle weakness, impaired mobility, and fatigue – that get worse with age.
Sadly, muscle dystrophies are often diagnosed already in children, dramatically reducing their life expectancy. Some of them even die before reaching their teenage years.
Currently, no treatment is available for muscle dystrophy, as these conditions are caused by genetic changes that affect the messenger RNA (mRNA).
Avidity Biosciences has developed a potential therapy that uses an RNA/antibody complex to treat muscular dystrophy at the mRNA level.
Because the mechanism of action is quite challenging to understand, they asked us to prepare an animated video to explain it to doctors, patients, and also to their investors.
We are happy to see that muscular dystrophy may eventually be treated, reducing the symptoms and improving the quality of life in patients of all ages.
The hand-drawn style works very well with animations showing processes at the nuclear level (genes / DNA / RNA / protein production). As such processes are very complex and involve many elements, reducing the complexity is necessary to focus on the main message. Black and white color palette with just a few accent colors enhances simplicity.
Myotonic dystrophy is a hereditary disease that leads to muscle weakness, impaired mobility, heart complications and fatigue. It is a progressive disease that results in decreased quality of life and life expectancy.
Myotonic Dystrophy Type I is caused by hundreds or thousands of nucleotide repeats at the end of a gene called DMPK.
When the DMPK gene is transcribed into RNA, the RNA also carries the nucleotide repeats at its end. These repeats form a hairpin loop structure that is not normal and makes the DMPK RNA toxic to the cell. The toxic hairpin loops prevent a protein called MBNL from performing its normal function.
Normally, MBNL guides RNA processing and helps the cell make proteins. In myotonic dystrophy, MBNL sticks to the hairpin loops and can’t perform its job. Many proteins within the muscle are made incorrectly, affecting muscle strength and mobility, leading to muscle weakness, cardiac conduction defects, and other symptoms of myotonic dystrophy.
To treat myotonic dystrophy, Avidity Biosciences has designed a specific oligonucleotide (or oligo) that binds to the toxic DMPK RNA, marking it for destruction by cellular enzymes. When the toxic DMPK RNA is destroyed, MBNL is released and can again process the RNA of muscle proteins, replacing the incorrect proteins with correct ones. Correcting the muscle proteins may lead to improvements in muscle health and strength.
However, cells do not take up oligos well, making their therapeutic use difficult. Avidity Biosciences has developed antibody-oligonucleotide conjugates (AOCs). AOCs can deliver oligonucleotide therapeutics to muscle cells. The antibody part of the AOC binds to muscle cells. When the cells take up the antibody, the oligos are taken up as well. Using AOCs, oligos can enter the cell much more effectively.
Avidity is pioneering the development of AOC 1001, the first potential disease-modifying therapy to be investigated for Myotonic Dystrophy. Avidity expects to initiate a Phase 1/2 clinical study in Myotonic Dystrophy patients by the end of 2021.
AOCs can also deliver therapeutic oligos designed to treat other muscle diseases.
Find out more at Avidity Biosciences website
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