RNA Therapy Holds Promise for Treating SMA and Other Rare Diseases

by Jodee Redmond from In the Cloud Copy


Emma Larsons parents were not particularly concerned when their daughter wasnt standing or walking by her first birthday. They figured that plenty of children had not reached this developmental milestone by 12 months and that Emma would do these things on her schedule. The following month, Emmas legs started buckling when she tried to stand up and she started covering less ground when she was crawling across the floor. Her parents also noticed that she was having trouble holding her head up. 

The change in Emmas abilities led to consultations with doctors and several tests. In July 2014, the family was told that Emma had SMA (spinal muscular atrophy). 

What is SMA? 

Spinal muscular atrophy is a disease that attacks the motor nerve cells located in the spinal cord. Over time, it affects a patients ability to eat, walk, or breathe independently. SMA is a leading genetic cause of death for infants.  

It is a rare disease, affecting about one in 11,000 children. Approximately one in 50 people in the US is a genetic carrier of SMA.  

SMA occurs when the survival motor neuron gene 1 (SMN1) mutates. In a healthy individual, the SMN1 creates a protein required for nerves that control muscles to function normally. When this protein is not present, the nerve cells cant function and will die. As a result, the muscles become weakened, which is crippling and sometimes fatal for the patient.  

A person living with SMA has trouble performing basic functions, like swallowing and breathing, although they have no issues with their cognitive abilities. 

Altering Inactive Gene Key to Treating SMA 

Adrian Krainer, a biochemist and molecular geneticist working at Cold Spring Harbor Laboratory, has been looking at SMA on a genetic level since 2000. He understood that the disease develops from either a missing or a mutated gene (SMN1). At the same time, he knew that there is a corresponding inactive analog of SMN1 called SMN2.  

By 2004, Krainer had started working with Frank Bennett from Ionis Pharmaceuticals. Together, they were working on a drug that would alter SMN2 in SMA patients. The goal was to restore SMN protein function and stop the disease from progressing. To reach this goal, the scientists used antisense oligonucleotides. 

Modified RNA Key to Altering Faulty Gene

Antisense oligonucleotides (ASOs) are small strings of RNA or DNA. They have been chemically modified and are designed to focus on RNA strands produced by a defective gene and alter that genes expression. In other words, ASOs bind to a particular section of RNA to produce proteins that can cause disease. (ASOs can also be used to make a piece of RNA stop producing disease-causing proteins.)  

Krainer, Bennett and their research colleagues worked for several years to find a drug that would work. They were successful in developing a medication for SMA and called it nusinersen. The medication was tested in human trials starting in 2011 and approved by the US Food and Drug Administration under the brand name Spinraza in 2016.  

It is given to a patient by injection into the cerebrospinal fluid (clear fluid surrounding the spinal cord). Once injected, the medication begins to work on the inactive motor gene to manufacture SMN.  

Spinraza has been used to treat patients in 40 countries. Twenty-five newborns diagnosed with severe cases of SMA were given the drug and at age four they were developing normally. ASOs are now being considered to treat other neurological diseases such as Huntingtons disease and amyotrophic lateral sclerosis (ALS). 

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