It Just Makes “Antisense:” Using Genetic Medicine to Treat Rare Diseases


As previously published in Scientific American, slightly after her first birthday, Emma Larson lost the use of her legs and started experiencing difficulty crawling. She was diagnosed with spinal muscular atrophy (SMA) in 2014. SMA is caused by a mutation in the SMN1 gene. Her body lacked enough survival motor neuron (SMN), a protein that would help strengthen and maintain her motor function. But after researchers in Cold Spring Harbor, NY created nusinersen, an antisense oligonucleotides medication, things changed – not just for the Larson family, but for those with SMA across the globe.

After 3 injections of nusinersen into her spinal fluid, Larson was crawling down the hallway. The drug, branded as Spinraza, has helped 25 newborns with SMA develop at a comparable rate. Learn more about spinal muscular atrophy here.

While antisense therapy has been controversial throughout the ages, recent research has shown that ASOs can be extremely helpful in managing neurodegenerative diseases. Read the research published in the Annual Review of Neuroscience. 

What are ASOs?

Antisense oligonucleotides (ASOs) are single-stranded DNA molecules that can be used to stop the spread of a targeted gene, usually one with a mutation. ASOs can bind to RNA to prevent a mutated protein from being produced, therefore assisting with the treatment of certain genetic disorders.

ASOs were discovered more than 40 years ago, but have been slow to be embraced by the medical community. In part, this is because it has previously been unclear how antisense therapy may help patients.

But the tides are turning for ASOs. Brett Monia, CEO of Ionis, states that:

“Antisense is tailor-made for diseases that have a genetic cause. It’s the epitome of precision medicine.”

Because of its ability to be customized for each patient and their specific disease or disorder, antisense has the ability to address rare diseases right at the source: genes.

How ASOs Work


Every person has DNA. DNA has four bases. The first is adenine (A), which always links to thymine (T). Guanine (G) always links with cytosine (C). RNA encodes the genetic material to create proteins needed to help the body to run.

Sometimes, however, the proteins come out incorrectly. They may have mutations or variations, or be over- or under-produced. While some medicines, such as those using monoclonal antibodies, attempt to use the body’s natural immune system to target these issues, ASOs want to replace the RNA before any issues occur. 

Why Antisense Now?

Researchers were long looking into the efficacy of ASOs. Modification of ribose sugar in ASOs’ RNA and DNA reduced the necessity for a higher dose of medication. Chemically modifying other areas of ASOs allowed them to become safer to take. Researchers discovered that specific targets for rare diseases were the easiest way to craft ASOs.

New Drugs and Clinical Trials

Hereditary nerve damage can be treated by RNAi drug Onpattro, or ASO drug Tegsedi.

Exondys 51 has shown to have some improvement for patients with Duchenne muscular dystrophy. Duchenne muscular dystrophy causes muscle weakness and degeneration, as well as issues with fine motor skills. Gene mutations keep dystrophin from being developed, but Exondys 51 has given patients increased dystrophin. The drug is still in its regulatory phase. Learn more about Duchenne muscular dystrophy.

RG6042 is in a phase 3 clinical trial for Huntington’s disease

There are current clinical trials designed to treat two forms of amyotrophic lateral sclerosis (ALS). The first is caused by a mutated SOD1 gene and the second from a mutated C9orf72 gene. Learn more about ALS here.

Antisense Therapies and Patient Stories

Emma Larson, now in first grade, can move around using her wheelchair. But ASOs have not only done great things for Emma.

Jaci Hermstad

Jaci Hermstad is a 26-year-old Iowan woman with a rare form of ALS caused by a FUS gene mutation. ALS is a neurodegenerative disorder causing dizziness, issues with breathing, and an inability to move muscles across the body.

ALS has long been a part of Jaci’s life, as her sister passed away from the disease when Jaci was 17. However, thanks to a tailor-made antisense medication, Jaci has regained some movement. Most notably, she is now able to move her arm again.

Mila Makovec

Nine-year-old Mila Makovec has Batten disease, a lysomal storage disorder which causes lipopigments to build up in body tissues. These lipopigments cause issues in the brain and nervous system. This can lead to seizures, a loss of motor skills, and personality changes. Learn more about Batten disease here. 

Mila started losing her motor skills and vision around age four, and testing showed one impaired gene. However, neurologist Timothy Yu discovered that Mila’s mutation was actually caused by a transposon, a gene that moves into a spot in the genome where it shouldn’t be.

It took Yu less than a year to use antisense oligonucleotides to create milasen. When she got her first dose, she was having up to 30 seizures daily and had lost all vision. After five months of milasen treatments, Mila was having seizures lasting only seconds. After a year, she was able to start walking up stairs.

Looking to the Future

As research into ASOs continue, the next step is to understand how to make the drugs even more targeted to tissues of interest throughout the body. For example, ASOs cannot cross the blood-brain barrier. But a lumbar puncture used to deliver the medication to mice modeling Huntington’s disease showed improvement by reducing levels of huntingtin protein.

By performing genetic testing or genomic sequencing, researchers will only get closer to treating not just the symptoms of rare diseases, but their causes.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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