One of the challenges in developing elegant therapies that act on the underlying cause of a rare genetic disease is that sometimes the treatments may work only on patients with a specific genetic variant driving the condition.

For instance, the rare lung disease cystic fibrosis is caused by mutations in the CFTR gene, but there are nearly 2,000 known mutations. While the drug Kalydeco can be an effective treatment for the condition, it only works on patients who have a small subset of those mutations.

A new study published in the Nature Genetics, though, found a different situation. The researchers discovered patients with four different rare, adult-onset, neurodegenerative diseases who share the same type of genetic mutation. As such it opens up an intriguing idea that one therapy might be developed to treat multiple genetic diseases.

In the early 2000s, the condition fragile X tremor/ataxia syndrome was discovered be caused by what is termed a “noncoding expanded tandem repeat mutation on the X chromosome.” In simple terms, it had three letters of the genetic code—CGG—an unusual number of times. Everyone has such repeats and they can occur anywhere. When they happen dozens or hundreds of times, they can cause a disease.

The research team had a patient with this condition, but they found other patients with adult-onset neurodegeneration. These patients had similar symptoms, such as cognitive impairment, uncontrolled movement, loss of balance, limb weakness, or difficulty swallowing.

Knowing about the CGG repeat in the patient with fragile X tremor/ataxia syndrome, they decided to look for it in these other patients. It wasn’t found on the X chromosome but they decided to see if they could find it elsewhere.

Using next-generation sequencing, the researchers sequenced patients’ and healthy people’s genomes in short, overlapping and broken stretches. Shinichi Morishita, a computational biologist from the Department of Bioinformatics and Systems Biology, University of Tokyo, developed a computer program to sort all of those short sequences and search for ones consisting of just CGG over and over again.

The researchers then used a healthy human genome to help locate the regions where each of those repeats occurred in these patients. They then zeroed in on areas where the patients had a large number of CGG repeats but the healthy people didn’t. Doing so allowed the researchers to sequence a long stretch of DNA to identify the specific gene and place within the gene where the CGG repeat could be found.

What the researchers discovered was that in these four cases, the CGG repeat mutations occurred in distant, seemingly unrelated areas of the genome.

They suggest gene silencing therapies could be a therapeutic strategy for addressing these conditions with the added benefit that one solution might work for all cases.

One of the challenges in developing elegant therapies that act on the underlying cause of a rare genetic disease is that sometimes the treatments may work only on patients with a specific genetic variant driving the condition.

For instance, the rare lung disease cystic fibrosis is caused by mutations in the CFTR gene, but there are nearly 2,000 known mutations. While the drug Kalydeco can be an effective treatment for the condition, it only works on patients who have a small subset of those mutations.

A new study published in the Nature Genetics, though, found a different situation. The researchers discovered patients with four different rare, adult-onset, neurodegenerative diseases who share the same type of genetic mutation. As such it opens an intriguing idea that one therapy might be developed to treat multiple genetic diseases.

In the early 2000s, the condition fragile X tremor/ataxia syndrome was discovered be caused by what is termed a “noncoding expanded tandem repeat mutation on the X chromosome. In simple terms, it had three letters of the genetic code—CGG—an unusual number of times. Everyone has such repeats and they can occur anywhere. When they happen dozens or hundreds of times, they can cause a disease.

The research team had a patient with this condition, but they found other patients with adult-onset neurodegeneration. These patients had similar symptoms, such as cognitive impairment, uncontrolled movement, loss of balance, limb weakness, or difficulty swallowing.

Knowing about the CGG repeat in the patient with fragile X tremor/ataxia syndrome, they decided to look for it in these other patients. It wasn’t found on the X chromosome but decided to see if they could find it elsewhere.

Using next-generation sequencing, the researchers sequenced patients’ and healthy people’s genomes in short, overlapping and broken stretches. Shinichi Morishita, a computational biologist from the Department of Bioinformatics and Systems Biology, developed a computer program to sort all of those short sequences and search for ones consisting of just CGG over and over again.

They then used a healthy human genome to help locate the regions each of those repeats occurred in these patients. They then zeroed in on areas where the patients had a large number of CGG repeats but the healthy people didn’t. Doing so allowed the researchers to sequence a long stretch of DNA to identify the specific gene and place within the gene where the CGG repeat can be found.

What the researchers discovered was that in these four cases, the CGG repeat mutations occurred in distant, seemingly unrelated areas of the genome.

They suggest gene silencing therapies could be a therapeutic strategy for addressing these conditions with the added benefit that one solution might work for all cases.

“Because the mutations causing the diseases are so similar,” said Hiroyuki Ishiura, assistant professor from the University of Tokyo Hospital and lead author of the Nature Genetics paper, “in the future, all these patients might benefit from the same treatment.”
 

Photo: MRI brain scans of patients with similar rare neurodegenerative symptoms. Image by Hiroyuki Ishiura and Shoji Tsuji

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