Here we go again.

This week, investors may have seen that a new gene editing technique will soon be available to scientists attempting to engineer DNA for human health applications. Dubbed "prime editing," some have called it a game-changer due to its inherent advantages over more commonly used CRISPR techniques. It has the potential to correct up to 89% of disease-causing mutations and is engineered to make more precise edits than other gene editing techniques. And it all belongs to a new start-up: Prime Medicine.

But despite all of the media hype, prime editing has one enormous problem that may make it impossible to commercialize: The molecular components are way too big to be delivered into cells using current methods. It's as if an automaker designed a car with an amazing interior, but forgot to add wheels.

The "big" obstacle facing prime editing doesn't necessarily mean CRISPR Therapeutics (NASDAQ:CRSP), Editas Medicine (NASDAQ:EDIT), and Intellia Therapeutics (NASDAQ:NTLA) will have smooth sailing ahead, but it does highlight an important facet of gene editing technologies that investors can't overlook: delivery.

Cutting both strands of DNA is bad. Image source: Getty Images.

Healthcare investors are probably familiar with the basics of how CRISPR gene editing works by now, but a little refresher can't hurt.

The payload comprises a guide RNA and a cutting enzyme such as Cas9. The guide RNA helps the payload locate the target sequence of DNA that will be edited. Once located, the payload binds to the target sequence of DNA, and the cutting enzyme makes a double-stranded break (meaning it cuts through both strands of DNA) to remove or insert DNA.

But there are problems. The guide RNA and cutting enzyme aren't always 100% accurate, and can sometimes edit the genome relatively far from the target site. That can introduce changes to the genome, which can be harmless -- or potentially harmful.

An even larger problem is that traditional CRISPR gene editing techniques make double-stranded DNA breaks that require one of two natural DNA repair mechanisms to patch up. Unfortunately, there can be significant consequences to this, such as allowing a dormant cancer cell to proliferate and reduced editing efficiency. This problem isn't alleviated by using different cutting enzymes, such as switching from Cas9 to Cas12.

While CRISPR Therapeutics, Editas Medicine, and Intellia Therapeutics have gone all-in on CRISPR-Cas systems, many scientists aren't confident that the technique will deliver on its promise in a clinical setting. But the learning experiences in the lab have spurred a search for new gene editing techniques that don't make as many off-target edits and don't make double-stranded breaks. Prime editing is the latest tool.

Cutting one strand of DNA is better. Image source: Getty Images.

Prime editing makes some notable modifications to the traditional CRISPR-Cas setup. The cutting enzyme, Cas9, has been modified to only cut one strand of DNA. The guide RNA deployed also contains the instructions for the desired edit. And a second enzyme, called reverse transcriptase, has been added to the payload to write the desired edits into the exposed strand of target DNA.

The changes allow prime editing to change any DNA base -- A, T, C, or G -- into any other. Prime editing has also been used to insert up to 44 base letters and delete up to 80 base letters from target DNA in limited studies. It may not seem like much considering the human genome contains over 3 billion base pairs, but the characteristics described above could allow the new technique to correct up to 89% of disease-causing mutations in humans.

The versatility is pretty amazing, but the problem is that prime editing payloads -- comprising two enzymes and a longer guide RNA -- are too large to be delivered with today's delivery vehicles, such as adeno-associated viruses (AAV); after all, enzymes are big. The field of gene therapy only recently overcame the hurdle of delivery, and gene editing is still trying to figure it out.

CRISPR Therapeutics has (perhaps wisely) kicked that can down the road by focusing initial efforts on ex vivo editing, or editing cells in a controlled environment outside of the human body, where delivery is somewhat less complicated. Editas Medicine has taken up the mantle of being the first to try in vivo editing, or editing cells directly in the human body. It's using AAV delivery vehicles initially.

Meanwhile, Intellia Therapeutics has fallen out of favor with investors because its slow-and-steady approach won't let it enter clinical trials until 2020 or 2021. But investors may be missing the point. Rather than plowing ahead with AAV delivery, the company is working to develop new and novel delivery systems based on lipid nanoparticle (LNP) tech licensed from Novartis. It could end up being the main differentiator in the CRISPR gene editing space, and the move is entirely aimed at solving the tricky problem of delivery.

There's also Precision BioSciences (NASDAQ:DTIL), which has a proprietary gene editing system called ARCUS. The tech is completely shielded from CRISPR patent disputes, doesn't make double-stranded DNA cuts, is ahead of CRISPR Therapeutics in an important clinical area, and can diversify its revenue by forging into agriculture or industrial biotech. It relies on AAV delivery vehicles.

Simply put, at a time when gene editing techniques are attempting to figure out the best solution to overcome delivery obstacles, prime editing went all-in on optimizing other characteristics of the tool, while betting the delivery problem will solve itself. That's a risky bet.

Image source: Getty Images.

Luckily for scientists and investors, the swift rise of CRISPR gene editing in research settings has led to the development of robust testing tools. That should shorten the learning curve for researchers wanting to know whether or not prime editing is going to live up to the hype -- or overcome its big delivery problem.

Nonetheless, the media hype highlights that individual investors need to be more selective in their approach to gene editing stocks. Tools that make double-stranded breaks (read: CRISPR) are likely to have a high rate of failure, but ex vivo applications in engineering immune cells could yield success. That would bode well for CRISPR Therapeutics and Precision BioSciences.

The delivery problem will make in vivo editing much more difficult, which could be a problem for Editas Medicine's lead drug candidates and future areas of focus of CRISPR Therapeutics. Intellia Therapeutics is hopeful its LNP approach could solve the problem, but it's too soon to know.

That said, there's one gene editing technique that could strike a balance between traditional CRISPR-Cas systems and prime editing: base editing. It was developed by the same lab that pioneered prime editing and belongs to a start-up called Beam Therapeutics, and Editas Medicine may already have one foot in the doorto licensing the tech. Then again, the gene editing space is very young and rapidly evolving, so investors cannot dismiss the inherent risks of owning gene editing stocks.

More:
There's Yet Another Gene Editing Technique, but It Has 1 Glaring Problem - Motley Fool

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