If you're born today with the blood disorder beta thalassemia, it's a life sentence. The genetic condition - the result of a single mutation on chromosome 11 - cripples the body's ability to produce enough red blood cells. Severe cases require a lifetime of blood transfusions to fight off anemia, and there's no cure.
But a new, possibly safer method for fixing bad genes could change that - and offers a new way to treat other genetic diseases.
In a paper published this week in Nature Communications, a team of researchers from Carnegie Mellon University and Yale University describe how they cured mice with beta thalassemia using a groundbreaking method for altering mutated genes.
Gene-editing is a hot topic in medical research, especially a popular technique called CRISPR (pronounced "crisper"). With any type of gene-editing, the goal is to cut out the mutated portion of a cell's DNA and replace it with healthy "code."
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For decades, scientists relied on slow and expensive gene-editing methods accessible only to the best-funded research centers. But with the rise of CRISPR in 2012, fast and effective gene-splicing can be done for as little as $30 in off-the-shelf materials. Now scientists say they can do even better.
Better than CRISPR?
Danith Ly, a professor of chemistry at CMU and co-author of the paper, told Seeker that his team's new gene-editing method offers two significant advantages over the much-hyped CRISPR. First, to repair a genetic mutation using CRISPR, scientists must use an enzyme derived from bacteria to cut open the DNA.
"With CRISPR, you're delivering a molecular 'scissor' into the cells," Ly told Seeker. "That scissor, in addition to cutting wherever you want it to cut, is going to cut other places as well."
These "off-target effects" can result in damage to related genes, which has the potential to spawn new diseases. Since the new CMU-Yale technique triggers the body's own repair enzymes to make the cut, the chances of an off-target cut are extremely low, less than one in 500,000 according to Ly.
The second major advantage of the new CMU-Yale technique is that it can be executed en vivo - inside the patient's body - using nothing more than a regular IV. For CRISPR to work, cells must first be extracted from the patient, then all of the gene-editing is done ex vivo in a test tube. Once the healthy repaired cells are propagated, they're returned back to the body.
"We don't have to do any complicated extracting of bone marrow, putting it in a dish, and introducing CRISPR enzymes or viruses," said Peter Glazer, professor of both genetics and therapeutic radiology at Yale, and principal investigator of the experimental technique. "After just four simple IV treatments, the anemia associated with beta thalassemia, a genetic blood disorder, was completely cured in the mice."
How it Works: Triple Helixes and PNA
The CMU-Yale method relies on three novel discoveries that were decades in the making. The first involves an oddity called triple-helix DNA.
"Normal DNA is a double helix where two strands wind around each other," said Glazer. "In rare cases, DNA can also form a triple helix where another piece of DNA winds around that duplex DNA in one of the grooves and form a three-stranded structure."
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Glazer discovered that the weird shape of triple-helix DNA signals the cell's own repair enzymes to cut off the extraneous strand. What if Glazer could send a cell into repair mode by creating his own triple helices? He began working with bioengineers to experiment with different synthetic materials that could bind to DNA and mimic the triple-helix structure.
That's where PNA comes in. Peptide nucleic acid (PNA) was first synthesized in Denmark in 1991, but while it was useful in other types of genetic research, scientists couldn't figure out how to make it bind to DNA at a specific target site. For the past 10 years, Ly at CMU has been tweaking the PNA recipe. The result is a custom-made molecule called gamma-PNA - only 25 nucleotides long - which can recognize and target any sequence of DNA that Ly wants.
"We're the only lab that does that," Ly added. "There are no other molecules that can recognize double-strand DNA the way that gamma-PNA does."
The gamma-PNA is carried into the bloodstream by an FDA-approved nanoparticle developed by Mark Saltzman, also at Yale. Once inside the body, the gamma-PNA leaches out of the nanoparticle and binds to a nearby cell's DNA, forming a triple helix precisely at the site of the mutated gene. Then out come the cell's repair enzymes to make a cut.
Here's where the CMU-Yale method and CRISPR converge. Both techniques use a piece of healthy donor DNA to "re-code" the faulty gene. It works similar to genetic recombination during sexual reproduction, when mom and dad's DNA combine to create the baby's new genetic instruction manual. Here, the donor DNA provides a blueprint for the replacement gene and the mutation is reversed.
The lab mice cured by the CMU-Yale technique were engineered to carry the human blood disease beta thalassemia, a genetic disorder which in severe cases requires a lifetime of blood transfusions. Ly is confident that the same technique could be used to cure sickle-cell anemia, another debilitating condition caused by a single mutated gene.
But how far away are we from trying out these life-changing genetic fixes on people? Ly is in the process of filing an application with the FDA to begin human trials of his CRISPR rival.
Meanwhile, Ly said that researchers around the world are working hard to limit the potential "off-target effects" of CRISPR, which is otherwise a very powerful tool for modifying and repairing genes.
We may still be a decade away from gene-editing becoming a routine medical procedure, but there's growing hope that soon we'll have not just a treatment for some of the world's deadliest genetic conditions, but a cure.
Image: A peptide nucleic acid developed at Carnegie Mellon is part of a gene editing system that has cured a blood disorder in mice. Credit: Carnegie Mellon University WATCH VIDEO: What is CRISPR & How Could It Edit Your DNA?