Little girl receives breathing treatment
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Antisense oligonucleotides, or ASOs, could be used to provide personalized therapy for cystic fibrosis, according to new research by the laboratory of Cold Spring Harbor Professor Adrian Krainer.

His team has found how to use ASOs to make more of an imperfect, but still functional, version of CFTR for patients with a specific mutation—W1282X. The discovery sets the stage for a new therapeutic approach that may help reduce CF symptoms and improve patients’ quality of life for certain patients.

Their report was published recently in Nature Communications.

Krainer is known for using ASO technology to develop the first FDA-approved treatment for spinal muscular atrophy (Spinraza)—a drug that has helped more than 11,000 patients. He thinks in the future ASOs may increasingly become a way to tailor therapies specific to an individual’s unique genetic mutations.

“If more of this type of drug, ASOs, are approved,” Krainer says, “I wouldn’t be surprised if in the not-so-distant future ASOs become a routine way to make personalized medicines.”

More recently, his lab has focused on cystic fibrosis, in which patients do not make enough the protein CFTR. An estimated 40,000 children and adults are living with cystic fibrosis in the United States alone, and 105,000 people have been diagnosed with the condition across 94 countries. According to Business Insights, the global cystic fibrosis market size stood at USD 5.12 billion in 2019 and is projected to reach USD 31.88 billion by 2027.

Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in developing a therapy for cystic fibrosis caused by the W1282X mutation in the CFTR gene. This is the 6th most common CF-causing mutation, causes a severe form of CF and is present in 1.2% of patients worldwide. CFTR-W1282X truncated protein retains partial function, so increasing its levels by inhibiting NMD of its mRNA will likely be beneficial.

Because NMD regulates the normal expression of many genes, gene-specific stabilization of CFTR-W1282X mRNA expression is a better goal than general NMD inhibition. ASOs designed to prevent binding of exon junction complexes downstream of premature termination codons attenuate NMD in a gene-specific manner.

In this paper, Krainer and his team describe cocktails of three ASOs that specifically increase the expression of CFTR-W1282X mRNA and CFTR protein upon delivery into human bronchial epithelial cells. This treatment increases the CFTR-mediated chloride current. They write that their results, “Set the stage for clinical development of an allele-specific therapy for CF caused by the W1282X mutation.” The study was led by Young Jin Kim, a former MD, PhD, student in the Krainer laboratory.

The imperfect CFTR protein is a result of a gene mutation. It causes cells to receive the wrong instructions for making the protein. The faulty instructions are eliminated and the protein isn’t made, since in general, imperfect proteins may be disruptive. Krainer’s ASOs trick cells into following the faulty instructions and making the imperfect CFTR protein. His team found that, in this case of CF, having an imperfect version of the protein is better than having none at all. Their method improved the function of lung cells, suggesting the ASO strategy could improve symptoms in CF patients with this mutation.

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