Nav: Home

Designing gene therapy

March 31, 2016

Scientists at EMBL have increased the efficiency of a genome-engineering tool called Sleeping Beauty, which is showing promise in clinical trials of therapies for leukaemia and lymphoma. In a study published today in Nature Communications, they reveal structural information that they hope will ultimately result in better patient outcomes.

"Based on the structure, we designed new variants that are already 30% more efficient than the most efficient ones currently available," says Orsolya Barabas, who led the work at EMBL. "That may not sound like a lot, but for patients with only a few months' prognosis, waiting 3 weeks for a treatment is better than waiting a whole month."

Sleeping Beauty is a transposon, or 'jumping gene', currently being used in clinical trials for B-cell leukaemias and lymphomas. In these treatments, Sleeping Beauty is used to insert a gene into T-cells - white blood cells that help to track down and eliminate threats such as disease-causing microbes - harvested from a patient. The genetically modified T-cells are injected back into the patient, where their new gene enables them to seek out and destroy the cancer cells. The technique is cheaper and easier to apply than current approaches, which mainly rely on modified viruses as deliverymen, so it is rapidly moving into clinical practice, and attracting investment from the pharmaceutical industry.

A bottleneck of this method is that it takes time to engineer and select the therapeutic T-cells. The quicker the T-cells can be modified and transplanted back, the better the treatment prognosis for the patients, and the lower the costs. Until now, however, efforts to increase the treatment's efficiency were educated guesses, based on the structure of similar molecules. Franka Voigt, a postdoc in Barabas' lab, determined the structure of Sleeping Beauty's active domain. Working with Zoltán Ivics' lab at the Paul Ehrlich Institute in Germany, the EMBL scientists then designed changes to that structure to make it work better.

More efficient than CRISPR

Transposons like Sleeping Beauty have advantages for therapies that hinge on inserting a gene, compared to other genome engineering approaches such as CRISPR/Cas9. Researchers can make CRISPR/Cas9 cut the genome at a specific point - making it ideal for eliminating genetic errors - but it doesn't insert any genetic material; the gene is added separately, and is only one of several options available to the cell's machinery to repair the cut. By contrast, Sleeping Beauty inserts the extra genetic material directly into the genome - and the EMBL scientists' enhancements now make it even more efficient.

"Ideally, you'd want to combine the targeting of CRISPR and the efficiency of Sleeping Beauty - but that's proving very, very difficult," says Barabas, "so it makes sense to pursue the applications that each is best at, at least for the time being."

Efforts to direct Sleeping Beauty to insert its cargo at specific locations have so far been unsuccessful. It inserts the extra genetic material at random, so there is a risk - albeit a small one - that the addition could disrupt the cell's genome. To minimise this risk, the therapies currently being trialled involve carefully selecting which T-cells to inject back into a patient, which takes time.

The scientists are continuing to design mutations to try to increase Sleeping Beauty's efficiency even further. In parallel, Barabas' lab strives to uncover the structure of the whole molecule bound to the DNA that it acts upon, as this could provide insights for further improvements. Such future improvements could make Sleeping Beauty-based therapies feasible for other conditions such as solid tumours, where the current versions of Sleeping Beauty are not efficient enough.
-end-


European Molecular Biology Laboratory

Related Genome Articles:

Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.
Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.
A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.
How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.
Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.
Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.
Why do we need one pair of genome?
Scientists have unraveled how the cell replication process destabilizes when it has more, or less, than a pair of chromosome sets, each of which is called a genome -- a major step toward understanding chromosome instability in cancer cells.
A new genome for regeneration research
The first complete genome assembly of planarian flatworm reveals a treasure trove on the function and evolution of genes.
Decoding the Axolotl genome
The sequencing of the largest genome to date lays the foundation for novel insights into tissue regeneration.
The Down's syndrome 'super genome'
Only 20 percent of foetuses with trisomy 21 reach full term.
More Genome News and Genome Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#544 Prosperity Without Growth
The societies we live in are organised around growth, objects, and driving forward a constantly expanding economy as benchmarks of success and prosperity. But this growing consumption at all costs is at odds with our understanding of what our planet can support. How do we lower the environmental impact of economic activity? How do we redefine success and prosperity separate from GDP, which politicians and governments have focused on for decades? We speak with ecological economist Tim Jackson, Professor of Sustainable Development at the University of Surrey, Director of the Centre for the Understanding of Sustainable Propserity, and author of...
Now Playing: Radiolab

An Announcement from Radiolab