New NIH viral vector flips the script on sickle cell disease gene therapy
Researchers at the NIH have rolled out a new vehicle for sickle cell gene therapy with higher speeds and better horsepower, potentially allowing vastly more efficient gene transfer and a much larger carrying capacity. The best part? Unlike current sickle cell gene therapy models, the NIH one doesn’t have to drive in reverse.
In mice and monkeys, the new vehicle was up to 10 times more efficient and had a carrying capacity – the amount of DNA it can haul – of up to 6 times that of the conventional vectors currently deployed in gene therapy trials across the country. Most notably, the new vector can read the therapeutic gene sequence forward rather than reading them backward — a counter-intuitive trick researchers had used to overcome long-running barriers to gene therapy but which sacrificed efficiency. The results were published open access in Nature Communications.
“Our new vector is an important breakthrough in the field of gene therapy for sickle cell disease,” said study senior author John Tisdale, chief of the Cellular and Molecular Therapeutic Branch at the National Heart, Lung, and Blood Institute (NHLBI). “It’s the new kid on the block and represents a substantial improvement in our ability to produce high capacity, high-efficiency vectors for treating this devastating disorder.”
Gene therapy trials for SCD have launched the past few years, bringing a handful of well-covered cases of patients responding strongly to the treatment, even as more data shows current techniques are no cure-all. One of the bigger longstanding questions, though, is how to best deliver the genetic fix.
The simple genetic underpinnings of the disease have been well-understood since the 1950s — one A-T substitution in the β-globin gene — and researchers have accordingly targeted it since the first gene therapy research in the 1980s. But the particular problems of building a proper vector for the hemoglobin gene, in addition to the myriad other obstacles to gene therapy broadly, have impeded progress.
The steps in gene therapy for sickle cell disease. National Heart, Lung, and Blood Institute
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The lentiviral vector bluebird bio has used to bring its sickle cell gene therapy to trial is a workaround to an early problem unique to sickle cell therapy. RNA splicing – a natural process critical to preparing the vector – will remove “introns” that are key to expressing the genes to produce hemoglobin. Developers have been able to get around this by using a vector that reads the DNA backwards, last gene to first. Most gene therapy techniques read as you would a sentence, first word to last.
The researchers also noted their vectors were cheaper to produce.