For years, gene therapy has been touted as the future of medicine. If we could only correct a faulty gene, a whole host of diseases—some previously deemed incurable—would disappear. But editing the human genome by removing or adding new DNA has proved a challenging venture. Below, we look at four types of gene editing currently in clinical trials, as well as the pros and cons of each.
Zinc Finger Nucleases
How it works: Zinc finger nucleases (ZFNs) are a kind of custom endonuclease. They are programmed to identify the correct portion of a DNA sequence, which is then cut out using an enzyme.
Pros: The very first programmable gene editing tool, ZFNs ushered in a new era of medicine. This technology can rapidly induce edits: it requires just one transfection experiment. Mutated cell lines can be eliminated in just eight weeks.
Cons: ZFNs can be challenging to design, particularly for new gene targets. They’re also a fairly expensive form of gene editing, and off-target cuts can occur.
A few companies: Sigma Aldrich (NASDAQ:SIAL) commercializes this technology. ZFNs are used by companies like Sangamo Therapeutics (NASDAQ:SGMO), which engineers them to have over 90 percent on-target efficiency.
Transcription Activator-Like Effector Nucleases
How it works: A Transcription Activator-Like Nuclease (TALEN) is made up of bacterial genetic material. The TAL protein seeks out the the defective gene and then an endonuclease severs the DNA strand so that the correct, functional material can be delivered.
Pros: Although similar to ZFNs, TALENs are far easier to design and program, as well as cheaper to produce.
Cons: The technology is best suited for diseases like cystic fibrosis, where only one gene is affected. Those illnesses that affect multiple genes are, for the moment, beyond this technology’s scope. And though TALEN gene editing is fairly accurate, off-target cuts can still occur.
A few companies: Cellectis (NASDAQ:CLLS, EPA:ALCLS) made headlines in 2015, when its experimental TALENs cancer treatment was used to successfully treat Layla Richards, a little girl with leukemia. As noted above, tackling these sorts of multi-gene diseases was thought to be outside of TALENs’ applications and plenty of people were watching to see whether Layla’s remission could last. So far, so good—in fact, a second baby was successfully treated with this therapy last year.
How it works: Using a vector virus not known to cause disease, researchers deliver functional copies of genes to cells that carry a defective or mutated version of it.
Pros: The adeno-associated virus (AAV), which is used as the delivery system for new genetic material, does not appear to cause disease in humans. It’s been approved for use in one product already and many more products are currently in clinical trials.
AAV gene therapies also seem to have fairly strong specificity: that is, they deliver genetic material to the intended place, although random incorporations do occasionally occur.
Cons: Generally speaking, people treated with AAV gene therapies do not develop an immune response attacking the virus or the modified cells—a definite positive. However, in recent studies, the virus has been attacked by CD8+ cells.
Given the virus’s small size, its coding capacity is also limited. As such, it is unsuitable for correcting larger genes, at least at the moment.
A few companies: Audentes Therapeutics (NASDAQ:BOLD) and AveXis (NASDAQ:AVXS) both work with AAV. The first focuses on serious rare diseases, like X-linked myotubular myopathy or Crigler-Najjar syndrome, while the latter’s lead candidate is intended to treat spinal muscular atrophy.
How it works: By synthesizing RNA molecules, researchers provide a map of sorts to cells—triggering the Cas9 enzyme to sever part of the DNA sequence. Genetic material can then be inserted or taken away.
Pros: It’s cheap and it’s quick—plus it has the potential to be extremely precise.
Cons: CRISPR-Cas9 technology is caught up in a patent dispute, which seems to have scared off some investors. In March 2016, for example, Editas Medicine’s (NASDAQ:EDIT) blockbuster stock performance came crashing down—just as the court proceedings got going.
But the patent dispute isn’t CRISPR-Cas9’s only drawback. “As with any new tech, there are lots of potential hitches,” Fiona Barry of BioPharm Insight told Life Science Investing News. “For instance, we don’t yet understand its specificity: does it clearly target the gene we want to interrupt, or does it have the potential to interrupt others?”
A few companies: Dharmacon, a division of GE Healthcare (NYSE:GE) makes use of this technology. So do Editas Medicine, Intellia Therapeutics (NASDAQ:NTLA) and CRISPR Therapeutics (NASDAQ:CRSP), three CRISPR-Cas9 based biotechs that went public in 2016.
More may be set to join them. With that in mind, investors might also want to watch a few of the private companies also built on CRISPR-Cas9 gene editing technology, like Caribou Biosciences or ToolGen.
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Securities Disclosure: I, Chelsea Pratt, hold no direct investment interest in any company mentioned in this article.