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Breaking the Rules of Biology to Beat Rare Genetic Diseases

Like a skipping record, our genetic code has thousands of regions known as microsatellites where short combinations of base pairs — adenine (A), cytosine (C), guanine (G), and thymine (T) — repeat. For the most part, these repetitions are harmless. But in recent years, scientists have made important insights into how they can sometimes expand too much and cause genetic diseases, such as Huntington’s disease (HD) and a form of amyotrophic lateral sclerosis (ALS). Collectively, some 40 conditions in total are caused by pathological expansions of these repeats.

As researchers delve deeper into their understanding of repeat expansion disorders, they’re continually surprised at how much of the science breaks the common rules of biology. “There’s so much in this area that’s bizarre or unexpected,” says Christine Bulawa, a Senior Director in Pfizer’s Rare Disease Research Unit, based at the Kendall Square research site in Cambridge, Massachusetts. “Part of the moral of the story is to really pay attention to the data, and when the data are strong but we don’t expect it — that’s actually where we have the most to learn.”

In an effort to accelerate discovery in repeat expansion disorders, Pfizer’s Innovative Target Exploration Network (ITEN) is working with academic researchers across the globe to adapt emerging biology to make new therapeutics. “Repeat expansions unquestionably cause a whole bunch of diseases,” says Stefan McDonough, Executive Director of Genetics at Pfizer, also based in Kendall Square. “And what genetics is showing is that there is a possible therapeutic strategy to modify this expanded DNA directly to prevent or arrest many diseases that are right now probably some of the worst we have.”

Read on to learn more about the “rule-breaking” science behind repeat expansion disorders.

Rule 1: Our DNA is set from birth and does not change.

Some of the earliest insights into repeat expansion disorders were made in patients with Huntington’s disease (HD), a fatal neurodegenerative condition marked by a buildup of protein plaques in the brain. Scientists found that HD patients shared a common trait: Within their HTT gene, they had a section of DNA nucleotide code, CAG, that repeated anywhere from 41 to 60 times, leading to the creation of potentially toxic proteins. In healthy people, CAG only repeats 10 to 35 times. But in HD patients, as the disease progressed, the expansions continued to grow in certain types of cells, such as neurons. “The data indicated that their DNA was changing in the neurons that had given rise to the symptoms, and not just a little bit. It was going from an expanded gene segment of 41 to thousands of repeats,” says Bulawa. In other words, even though the DNA in those affected brain cells doesn’t replicate (because those cells don’t divide), this phenomenon of somatic expansion — the rule breaker — can occur.

Part of the moral of the story is to really pay attention to the data, and when the data are strong but we don't expect it — that's actually where we have the most to learn. 

Christine Bulawa

Rule 2: Mutations on non-coding DNA regions can’t be linked to disease.

According to the classical central dogma of biology, DNA codes for RNA, which then codes for the proteins that are a primary means of cellular function. Besides the fact that that may only be true for 1 to 1.5% of the DNA base pairs within the genome, there’s much more to it when you look more closely at the composition of DNA: There are specific “regions” that code for protein, and those are separated by different regions that do not. As scientists began to discover repeat expansions on those non-coding regions of our DNA, they started exploring how mutations in these regions can also lead to dysfunctional proteins and disease. “According to classical biology, repeats on these non-coding regions should just get looped out,” says McDonough. “What we’re finding is that diseases are being caused by structures that are not included in the protein.”

Rule 3: The longer your repeat expansion, the earlier you’ll develop the disease.

For most of the repeat expansion diseases, the longer the length of your repeat expansion, the earlier the onset of disease. But recent studies have examined patients who deviate from this rule: They developed the illness much earlier or later than their repeat expansion lengths had predicted. Looking closely at these patients, scientists found they had certain modifiers or DNA repair mechanisms that either helped protect them from developing the disease or caused it to start earlier. “Some of these modifiers are helping people live longer,” says Bulawa. “We want to be able to mimic the protective modifier and apply it to a variety of repeat expansion diseases.”

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