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What Do We Know About C9ORF72?

In this episode of the Endpoints, Dr. Fernando Vieira explains what we know so far about C9ORF72, a gene which has been implicated in up to 40% of cases of familial ALS. C9ORF72 was discovered to be a cause of ALS 8 years ago but there is still a lot for researchers to learn about its unique characteristics. Dr. Vieira talks about some of the hurdles to overcome and what researchers are doing right now to try to address this mutation.  

C9ORF72 stands for chromosome 9 open reading frame 72. An open reading frame is a stretch of DNA that is known to be both transcribeable and translatable. In other words, it’s a stretch of DNA that can encode a protein.  The gene was first discovered to be implicated in cases of familial ALS in 2011 when researchers from the National Institutes of Health and the Mayo Clinic simultaneously published findings on C9ORF72.

Familial ALS accounts for just 10% of ALS cases. Within that 10% around 25-40% is made up of people with a mutation in the C9ORF72 gene.  Even though there is still a lot for researchers to learn on how the normal C9ORF72 protein is supposed to work, a lot of research has been done to characterize the mutation.

The C9orf72 genetic mutation is a hexanucleotide repeat expansion which means it is a replication of a normally occurring pattern of letters in the DNA sequence of a gene. To help visualize this, think of strands of DNA like sentences. Most genetic mutations that we know about are the equivalent of a misspelling in the genetic code that result in small tweaks to a protein’s structure that cause problems inside or around cells. However, a mutation in the C9orf72 gene, is like finding that a properly spelled word is occurring too frequently in a sentence.

Despite the identification of the gene over 8 years ago, and more recent work on its characterization, C9ORF72 remains a puzzle to researchers today. When considering the best treatment approach for C9ORF72 mediated ALS, some general neuroprotective approaches that work for other kinds of ALS, may work. There are also a number of researchers trying antisense approaches to tackle this type of hereditary ALS. 

Biogen, in partnership with Ionis, is moving forward with antisense molecules targeted at SOD1 and C9ORF72 ALS. In their C9ORF72 trial, specifically, they are aiming to reduce production of the toxic RNA or dipeptide repeat proteins. Other approaches include the targeting of small molecule drugs at these expanded RNA molecules aimed at either stopping them from interacting harmfully in the cell or making them go away. As we learn more and gain a better understanding of how the dipeptide repeat proteins are made and how they are toxic in cells we hope to reveal more interesting targets for drug discovery and drug development.

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