We Are About to Enter the Golden Age of Gene Therapy

Eleven years ago, gene therapy — where defective genes are snipped out of DNA and replaced with healthy ones — became a household name. A landmark paper proved that scientists could precisely manipulate DNA in ways previously thought unimaginable using CRISPR-Cas9, an editing tool adapted from the immune system found in some bacteria. Almost overnight, the idea of designer babies, kill-switch mosquitoes, and cancer-off buttons stormed into mainstream imagination.

Since then, gene therapy has experienced a complete renaissance, culminating this past November and early December when medical regulators in the U.K. and U.S. officially approved Casgevy, the first CRISPR-based gene therapy for treating two blood disorders: sickle cell anemia and beta-thalassemia (in the U.S., the new therapy has yet to be approved for the latter).

Casgevy is emblematic of gene therapy’s rapidly shifting expectations and direction. Numerous clinical trials are now underway across the globe, and we will undoubtedly see more and more gene-editing-based treatments making the approval list, changing the lives of countless individuals living with intractable health conditions and diseases.

“The future [of gene therapy] is very bright,” Kevin Davies, the executive editor of The CRISPR Journal and author of Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing, tells Inverse. “But I don’t don’t think anybody in the field wants to get too complacent because it was less than 25 years ago that we were riding a similar initial wave of enthusiasm for the technology.”

It’s true. Long before the Human Genome Project would ever decode a DNA sequence, ambitious scientists were spurred by advances in biotechnology and the early success of initial human trials. In 1990, then-4-year-old Ashanti DeSilva became the first person to be successfully treated with gene therapy. The treatment, a precursor of sorts to CRISPR-based gene therapy, cured her of a rare immune-related genetic disorder.

But those high hopes of tweaking genes to prevent or treat disease were suddenly dashed when, in 1999, a teenager named Jesse Gelsinger, who had a rare metabolic disorder, died within four days of receiving an experimental gene therapy at the University of Pennsylvania. In response, the U.S. Food and Drug Administration (FDA) suspended the university’s entire gene therapy program — which had been the largest in the world at the time — and launched investigations into 69 other gene therapy trials that were underway across the United States. Years later, when CRISPR entered the world, enthusiasm rose again — and here we are.

So what will this new wave — Gene Therapy 2.0, if you will — look like? Certainly, a promising frontier for tackling not only rare but common diseases and exquisitely precise gene-editing tools. With it, though, will come side effects, including exorbitant prices, barriers to access, and a lingering, gigantic cause for concern because once you edit an embryo, there’s no turning back. Here’s what 2024 and beyond has in store for our gene-edited future.

Better editing

In the early years of genetic therapy, scientists didn’t have many tools at their disposal to fix a gene (or genes) at the heart of a disease, Shoukhrat Mitalipov, director of Oregon Health and Science University’s Center for Embryonic Cell and Gene Therapy, tells Inverse.

If someone’s disease was due to a gene mutation or loss, Mitalipov says the fix was to introduce a synthetic, albeit normal copy of that gene with a virus stripped of its infectiousness but still retaining the ability to add new genetic information into DNA. With this new addition, a cell could then make a functional protein. While these essentially viral Ubers remain part of the gene therapy toolkit, the discovery and development of CRISPR-Cas9 gave scientists a more precise grip on the genetic engineering steering wheel.

CRISPR, or clustered regularly interspaced short palindromic repeats, originate from bacteria and archaea and is used by these microorganisms as an immune defense against viruses called phages. The CRISPR system also includes specialized enzymes called CRISPR-associated proteins (or Cas). Together, they look through and remove any genetic sequences that may have been inserted by a sneaky phage or other invader, keeping the microorganism safe from infection.

In 2012, researchers Jennifer Doudna and Emmanuelle Charpentier published a groundbreaking study detailing a novel CRISPR-Cas9 system they programmed to cut specific sites in isolated DNA. This was done using strands of RNA — a molecule that is like a working copy of DNA, containing the direct instructions for protein-making — guiding CRISPR-Cas9 to a specific genetic sequence.

Krishanu Saha, a bioengineer at the University of Wisconsin–Madison whose lab is working on gene therapies for treating blindness, says the precision allowed by CRISPR-Cas9’s programmability is its singular selling point.

“Traditional gene therapy, which we call gene augmentation, is essentially flooding the cell with extra copies of a normal gene; in some cases, this doesn’t work,” Saha tells Inverse. “We found in a few cases, it’s really important to destroy the mutant copy of the [gene] or fix the underlying mutation and that’s where you have to have the precision of CRISPR to go in and specifically do that.”

CRISPR has a unique drawback, however. When it goes in to patch up the bit of DNA as instructed, it does so by fracturing both strands of the DNA double helix. A cell is left to repair the breaks on its own, ideally using the synthetic DNA offered by the CRISPR-Cas9 system. But because it’s a klutzy repairperson, the cell may also introduce errors such as inserting or deleting DNA.

This is why the focus of the next generation of gene editing tools is to try to minimize, as much as possible, the risk of new mutations, says Mitalipov.

These tools include base editing, where specific base pairs — the building blocks of DNA — are swapped out without requiring a double-stranded break. Base editing was used in a recent gene therapy clinical trial treating individuals with a genetic form of high cholesterol called familial hypercholesterolemia. The gene-editing technique, which is based on CRISPR, was developed in 2016 by Harvard University’s David Liu, considered a founding pioneer of CRISPR.

Another CRISPR-based tool is a leveled-up version of base editing. Called prime editing (also co-invented by Liu), it can swap base pairs in addition to inserting and deleting without double-breaking the DNA helix.

More recently, a gene-editing tool called NICER developed by researchers in Japan is said to create little single-strand nicks that didn’t seem to cause mutations, according to a September 2023 Nature Communications study.

Despite the appeal of finer precision and avoiding inadvertent mutations, Mitalipov and Saha say it’s unlikely the original CRISPR-Cas9 system will be ousted or replaced entirely by these newer gene editors.

“Basically, you would have to look at the specific gene mutation and then decide what would be the best — it could be base or prime editing,” says Mitalipov. “So far, prime editing hasn’t been widely used. There’s only one or two labs [doing research] and nothing commercially available. So, it remains to be seen if [prime editing] is really going to be applicable.”

More targets

CRISPR-based gene therapies are being devised to treat all sorts of conditions and disorders, from neurological to autoimmune and cancers. Currently, the only FDA-approved therapy using CRISPR is Casgevy; others on the market, such as Luxturna for people with a rare genetic defect that often leads to blindness and Zolgensma for treating spinal muscular atrophy, use a disabled virus bearing a normal version of the target gene to cells.

There are over 1,500 clinical trials for gene and cell therapies registered with ClinicalTrials.gov, and federal regulators are hoping to approve several more in the coming years, reported FierceBiotech in April 2023.

Currently, the focus is treating disorders or diseases caused by mutations in single genes in somatic cells (the body’s non-reproductive cells). This route makes it easier to identify and target relatively straightforward biological mechanisms than cracking at multiple genes acting in complex and sometimes unpredictable ways with which tinkering may lead to unintended, potentially life-threatening consequences. Understandably, since the late 1990s, there’s been a reasonably high regulatory bar for the research a gene therapy requires to meet FDA approval.

However, that doesn’t mean more genetically complex diseases are off the table. Editing multiple genes is quite possible and regularly done with transgenic animals (as well as plants), says Saha. Attempting this engineering feat for human health will take extensive research to uncover the genetic pathways and interactions involved and figuring out how to safely target all these genes with minimal off-target effects.

In the future, we may see gene therapies used increasingly for common health problems, not only rare genetic diseases, says Mitalipov and Saha. For example, a recent clinical trial in people with familial hypercholesterolemia found that one gene therapy targeting a mutated gene behind the build-up of bad cholesterol slashed cholesterol levels on par with similar-acting pharmaceutical drugs. These findings offer a tantalizing glimpse of an exciting beginning for gene therapy within preventative medicine, promising that someday, a simple edit in your genome may protect you against high cholesterol and blood pressure or any other commonplace ailments.

Therapies for all

There’s another barrier that could ultimately prevent even the safest, most promising gene therapy from seeing the light of clinical day: cost. Luxturna, for example, was reported at a whopping $425,000 per eye back in 2018. It’s a bit of a bargain compared to the average million-dollar price tag for emerging gene therapies such as Casgevy, the gene therapy for sickle-cell anemia/beta-thalassemia. The gene therapy market itself was valued at $1.46 billion in 2020 and is estimated to reach over $5 billion by 2028, according to a report by Polaris Market Research.

“How do we get the pricing down is an outrageously important and unsolvable question,” says Davies of The CRISPR Journal. “Some will point to ‘Well, it’s early days, and as more of these therapies get approved, we start to see competition and prices drop’... but we see when companies get a monopoly on something, they seem more than willing to take advantage of the situation.”

Saha says there’s an active discussion within the scientific community about how to make gene therapy equitable within the low- and middle-income countries that make up the Global South. But how gene therapy accessibility will play out in the coming years is yet to be seen.

“One of the key questions in our analysis is, who’s at the table making these decisions? It’s a fairly easy critique to say that the people in the room are not representative in various ways, perhaps Global North versus Global South, socioeconomic, scientific expertise versus the lay public,” says Saha. “There are important questions about power and democracy and whose knowledge should drive policymaking that needs to be settled. I think the deliberation and the process are as important as the end set of guidelines or policies.”

Then there’s the dreaded ethical prophecy augured by science fiction in films like Gattaca, set in a world where genetic engineering and socioeconomic status go hand in hand. Both before and after the infamous incident involving Chinese scientist He Jiankui creating the world’s first CRISPR-edited human babies with a gene for HIV immunity, there have been strict worldwide regulations on any gene editing research involving embryos.

But scientists like Mitalipov are looking into using CRISPR to potentially adjust an embryo’s risk for disease. His own research at OHSU involves gene-editing germline cells — or reproductive cells that pass on genetic information to the offspring — in what Mitalipov calls “IVF gene therapy.”

He says such a technique could help improve the success of embryo implantation during IVF by creating stronger, more viable embryos. Mitalipov acknowledges, however, that there needs to be a robust regulatory framework in place before we can ever truly consider genetically engineered babies.

“In terms of regulation, we have to focus only on those 10,000 gene defects we know today that cause human disease,” says Mitalipov. “It could be easily mandated that gene therapies in embryos have to be towards severe disease in children.”

But that, and the rest of gene therapy’s optimistically bright future, remains hedged with abundant yet much-warranted caution.