Atlas-backed Generation Bio promises ‘druglike’ gene therapy

DNA research
Generation Bio's first targets will be diseases of the liver.

The gene therapy sector has a new player—Generation Bio—which promises to provide safer, more controllable treatments that do away with the need to use viruses for delivery.

Backed by Atlas Ventures with a $25 million series A and headed by ex-Sobi CEO Geoff McDonough, Generation Bio says its lipid nanoparticle platform will allow it to offer the first genetic medicines that can be titrated to a particular dose—and redosed if necessary—like a conventional drug, and avoid the pitfalls of viral gene therapies such as generating immune reactions.

Generation Bio’s GeneWave tech is based on closed-ended DNA, which can travel from the cytoplasm of the cell to the nucleus without the use of a viral capsid and form stable ‘episomes’ that don’t integrate with the cell’s DNA but still have high levels of expression.

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The platform “can allow us to choose a low starting dose and incrementally redose each patient until they reach the desired level of gene expression—just like a traditional medicine with pharmacological properties,” McDonough told FierceBiotech. “Current gene therapy can only be dosed once, so the highest tolerated dose is typically administered to all patients.” That means some will receive too little, some too much, and there is no way to adjust accordingly. And if a patient doesn’t respond in the expected way to treatment, there isn’t a chance to try again.

“The immunogenicity associated with viral vector based gene therapies has limited the number of patients who could be treated due to pre-existing background immunity, as well as preventing the redosing of patients either to titrate to effective levels in each patient, or to maintain effects over the longer term,” he added.

There is also considerable variability between patients when it comes to expression of viral gene therapies, he tells us, and this makes selecting a dose a challenge. Meanwhile, a practical consequence is that gene therapies today cannot be delivered to newborns and young children, as their livers grow until early adolescence.

With GeneWave, “the lack of pre-existing immunity and ability to redose significantly expands patient access, including into pediatric populations who may require a subsequent dose upon tissue growth, and allows titration of the expression to effect in each patient.” As a bonus, it can also deliver larger genetic payloads than viral vectors like AAV.

The technology behind the startup’s platform stems from the work of gene delivery expert Robert Kotin, Ph.D., of UMass Medical School, who is a co-founder of Generation Bio. It uses lipid nanoparticles to carry the genetic payload, as these are preferentially taken up by the liver, so the biotech is directing its initial efforts to diseases that primarily affect that organ.

At the moment, the company is looking at four rare liver diseases: progressive familial intrahepatic cholestasis, phenylketonuria, glycogen storage disease 1a, and ornithine transcarbamylase deficiency. It hopes to take two candidates into IND-enabling studies in early 2019 and be in clinical trials “within two years,” said McDonough. Future programs could look at using the liver as a biofactory for missing proteins or enzymes in other indications such as lysosomal storage diseases and hemophilias.

Generation Bio spent a year in stealth mode, during which time it developed the platform and the capacity to manufacture and formulate GeneWave products in-house, and showed that it could achieve dose-dependent expression in the liver using animal models. The delivery system is also being modified to potentially target other key tissues such as the lung, retina, central nervous system, and muscle.

As it stands, the company is launching at a critical juncture for gene therapy, with the approval of the first product by the FDA—Spark’s Luxturna—and just-announced price and payment model for the therapy, which will serve as a road test for the commercial potential of high-price, high-benefit therapies.

“This is a breakthrough category of therapeutics which will continue to expand in the future,” McDonough said. “One aspect of our platform which is important to us is scale—by removing viral capsid from our manufacturing process we are increasing the scale and reducing the cost of our platform. Combined with the druglike properties of GeneWave, we aim to greatly expand the number and variety of diseases able to be addressed by gene therapy.”

With $25 million as a fighting fund, Generation Bio will be able to complete its proof-of-concept work in animals this year and add to its current head count of 22 in Cambridge, Massachusetts. A series B is planned before the end of the year.