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MicroRNA-based Gene Therapy Found to Improve Survival in Mouse Model

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MicroRNA-based Gene Therapy Found to Improve Survival in Mouse Model
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A single gene therapy treatment using microRNAs improved growth and development, and decreased lethal seizures in a mouse model of Lennox-Gastaut syndrome (LGS), a study has found. 

This proof-of-principle experiment supports the development of targeted therapies to help manage epilepsy and improve the quality of life for LGS patients and their families, researchers say. 

Their study, “RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model,” was published in the journal Molecular Therapy.

LGS belongs to a group of early-onset epileptic disorders known as developmental and epileptic encephalopathies, or DEEs. While some DEEs are caused by brain lesions or malformations occurring before or right after birth, genetic causes are also associated with the development of DEEs. 

Mutations in a gene called DNM1 have been identified as a genetic cause for some patients with Lennox-Gastaut syndrome. This gene contains the instructions for a protein known as dynamin-1 (Dnm1) that plays an important role in the proper function of nerve cell signaling. 

Before these mutations were discovered in humans, a type of mouse was found to carry a mutated version of the DNM1 gene, termed “fitful” (Dnm1-Ftfl), which represented the first link between DNM1 and severe epilepsy. 

Mice with one copy of the faulty gene experienced mild seizures from two to three months of age, and lived a normal lifespan, while those with two copies developed DEE-like symptoms by their third week. 

In contrast, mice that lack both copies of Dnm1-Ftfl did not experience seizures or other associated symptoms, suggesting that suppressing the mutated DNM1 gene in humans may be an effective treatment strategy for those with LGS. 

MicroRNAs (miRNAs), which are short pieces of RNA, can be used to suppress the activity of selected genes by binding to and blocking selected messenger RNAs (mRNA) — the molecule that carries the portion of the DNA code that contains the information to make a protein. 

To find out if miRNAs that target Dnm1-Ftfl affected LGS-like symptoms in mice that carry both copies of the mutated gene, a team of researchers based at the Columbia University Irving Medical Center, in New York, injected miRNAs, carried by a harmless virus called adeno-associated virus 9 (AAV-9), directly into the fluid that surrounds the brain and spinal cord (cerebrospinal fluid). 

The miRNAs were designed to specifically block one of two forms of the Dnm1-Ftfl mRNA — called DNM1a — which is expressed after birth, in contrast to DNM1b, which is made before birth. 

Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Mice were treated on the day they were born, and after two weeks, showed a significant reduction of DNM1a mRNA compared to mice given a injection that served as a control.  

While control mice began to display growth deficits eight days after birth and did not survive past 19 days, 75% of treated mice grew steadily at least until day 30, which was the study’s endpoint.

“Though a 30-day study endpoint was set to mark the end of the developmental stage and without expectations of the kind of success observed, the apparent vigor of treated mutants suggests even longer survival — a focus of future experiments,” the researchers wrote.

Overall, significant improvements in growth were observed by day 18 in treated mice compared with control mice. 

Both treated and control mice experienced seizures. However, treated mice had fewer events between days 14 and 18. By day 18, all control mice were unable to stay upright, while seizures and seizure-like events decreased in treated mice beyond this period. 

Treated mice also had significantly improved grip strength and motor development, and showed no signs of ataxia — involuntary and uncoordinated movements leading to abnormal walking and falls. 

A final detailed analysis of brain tissue from treated mice found decreased nerve cell damage and death, and less abnormal nerve cell activity on day 18, which was maintained and led to their survival until the study endpoint.

“In summary, this study serves as a strong proof-of-principle of the efficacy of [miRNA] therapy for the treatment of DNM1 DEE,” the researchers wrote. 

“Indeed, even conversion of a severely debilitating, untreatable disease to a more manageable form of epilepsy would immensely improve the quality of life and be transformative for patients and their families,” they added. 

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