Gene therapy comes of age: We can now edit entire genomes to cure diseases

For a long time, people thought HIV was incurable. The main reason was that HIV is a retrovirus, meaning that it inserts its own viral DNA into the genome of its host perhaps we could treat the symptoms of HIV, but many doubted it was possible to actually correct the genes themselves.Our techniques for slicing up DNA are very advanced when that DNA sits suspended in a test solution, but nearly useless when we need to accurately edit millions of copies of a gene spread throughout a complex, living animal. Technologies aimed at addressing that problem have been the topic of intense study in recent years, and this week MIT announced that one of the most promising lines of research has achieved its first major goal: researchers have permanently cured a genetic disease in an adult animal.

This is a proof of concept for something medicine has been teasing for decades: useful, whole-body genome editing in fully developed adults. Until recently, most such manipulation was possible only during early development and many genetic diseases dont make themselves known until after birth, or even much later in life. While breakthroughs in whole-genome sequencing are bringing genetic early-warning to awhole new level for parents, there are still plenty of ways to acquire problem DNA later in life most notably, through viruses like HIV. Whether were talking about a hereditary genetic disease like Alzheimers or an acquired one like radiation damage, MITs newest breakthrough has the potential to help.

A simplified schematic of the CRISPR system. RNA guides Cas9 in cutting at the CRISPR sequences.

In this study[doi:10.1038/nbt.2884], researchers attacked a disease called hereditarytyrosinemia, which stops liver cells from being able to process the amino acid tyrosine. It is caused by a mutation in just a single base of a single gene on the mouse (and human) genome, and prior research has confirmed that fixing that mutation cures the disease. The problem is that, until now, such a correction was only possible during early development, or even before fertilization of the egg. An adult body was thought to be simply too complex a target.

The gene editing technology used here is called the CRISPR system, which refers to the Clustered Regularly Interspaced Short Palindromic Repeats that allow its action.As the name suggests, the system inserts short palindromic DNA sequences called CRISPRs that are a defining characteristic of viral DNA. Bacteria have an evolved defense that finds these CRISPRs, treating them (correctly, until now) as evidence of unwanted viral DNA. Scientists insert DNA sequences that code for this bacterial cutting enzyme, along with the healthy version of our gene of interest and some extra RNA for targeting. All scientists need do is design their sequences so CRISPRs are inserted into the genome around the diseased gene, tricking the cell into identifying it as viral from there, the cell handles the excision all on its own, replacing the newly viral gene with the studys healthy version. The whole process plays out using the cells own machinery.

This is how MIT chose to visualize the process.

The experimental material actually enters the body via injection, targeted to a specific cell type.In this study, researchers observed an initial infection rate of roughly 1 in every 250 target cells. Those healthy cells out-competed their unmodified brothers, and within a month the corrected cells made up more than a third of the target cell type. This effectively cured the disease; when the mice were taken off of previously life-saving medication, they survived with little ill effect.

There are other possible solutions to the problem of adult gene editing, but they can be much more difficult to use,less accurate and reliable, and are generally useful in a narrower array of circumstances. CRISPRs offer a very high level of fidelity in targeting, both to specific cells in the body and to very specific genetic loci within each cell.

Tyrosinemia affects only about 1 in every 100,000 people, but the science on display here is very generalizable. While many diseases will require a more nuanced approach than was used here, many will not; wholly replacing genes in adult animals is a powerful tool, capable of curing many, many diseases. Not every cell type will lend itself as well to the CRISPR system, nor every disease; particularly, this study relies on the fact that corrected cells will naturally replace disease cells, improving their initial infection rate. That wont always be possible, unfortunately.

Theres also very little standing between this technique and non-medical applications can you drug test an athlete or academic for the contents of their own genome? These questions and more will become relevant over the next few decades, though their effects should be minuscule when weighed against the positive impacts of the medical applications.