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Gene Therapy 2.0: New Startups Aim to Fine-Tune Gene Delivery and Control

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MeiraGTx and Intrexon, for example, have been developing “genetic switches” to try to dial up or down the effects of gene therapy. Selecta Biosciences (NASDAQ: SELB) has a technology meant to suppress the immune reactions that can stifle gene therapies.

Generation Bio and Stoke are now in the mix as well. Generation is based on a discovery of former NIH scientist and UMass Medical School adjunct professor Robert Kotin. He published a paper in 2013 outlining the use of a type of genetic material—closed ended DNA, or ceDNA—for gene therapy. This eukaryotic DNA is packaged inside a lipid nanoparticle—essentially a fat bubble, a commonly used drug delivery tool—that is then injected into the body. The LNP dissolves once in the cytoplasm of a cell, and the ceDNA, on its own, heads to the nucleus to produce proteins.

The key, and potentially important difference between Generation’s approach and conventional gene therapy is it doesn’t involve the use of a virus. As CEO McDonough explains, that could provide three key advantages. The first is patients shouldn’t develop antibodies against the treatment. And because of this lack of immunity against the treatment, Generation can start with a low dose and administer it again if needed. Lastly, without the virus, the treatment could be cheaper to produce and easier to scale. “We’re just at the very narrowest beginning of what gene therapy and genetic medicine can do,” McDonough says. “I think this is really a pretty extraordinary jump forward based on where we are today.”

Cullis notes that Generation will still have to watch out for any unexpected safety problems from the use of its ceDNA, but added that its efforts are an example of the “growing awareness” in biopharma of tools other than viruses to broaden the use of genetic medicine. Intellia Therapeutics (NASDAQ: NTLA), one of the developers of CRISPR-Cas9 gene editing drugs, for instance, plans to use LNP technology to deliver a variety of its treatments. “I think you’ll find a fair number of them in the backroom are working on the non-viral approaches,” Cullis says.

Stoke, meanwhile, isn’t using gene therapy per se, but its approach is meant to do what gene therapies can’t: fine tune the level of protein made by treated cells. Stoke, formed by Adrian Krainer, the inventor of the RNA spinal muscular atrophy drug nusinersen (Spinraza), has found a way to efficiently identify segments of genes that can be targeted with a drug to dial up how much of a protein the body produces. Stoke then develops RNA drugs that target these key parts of the genome.

This precise control might be useful in, for example, autosomal dominant diseases, where mutations in just one copy of a gene reduces the amount of a particular protein. In these situations—genetic causes of epilepsy, for instance, Kaye explains—patients might need to get to normal levels of the protein, but overshooting it could be disastrous.

Both Generation and Stoke have much to prove about their respective approaches—they each expect to be in human trials in about two years. But that will still leave plenty of time for each to make their mark if gene therapy’s problems persist.

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