Gene therapy is changing how we treat disease

HN Summary

• Gene therapy is shifting medicine from treating symptoms to targeting disease at its genetic source, offering new hope for conditions such as Huntington’s disease, sickle cell disease and inherited neurological disorders. 

• Advances in viral delivery systems and gene-editing technologies like CRISPR are accelerating the development of therapies that could slow or even prevent disease progression. 

• Canadian researchers and biotechnology companies are playing a leading role in advancing gene therapy research, manufacturing and clinical innovation, with the potential to transform treatment for both rare and common diseases.

Gene therapy aims to target illness at its genetic source rather than manage symptoms. Here’s how the science works, and why researchers think it could transform medicine.

The neurosurgeon has no visual field. There is only a catheter, fed into the skull through a hole, no bigger than the tip of a crayon, and a set of coordinates that correspond to a target deep within the brain. A trajectory has been plotted from MRI scans taken with a stereotactic frame bolted to the patient’s head, a reference system that turns the brain’s interior into a 3D grid. 

The catheter advances along a pre-plotted line toward its destination: the striatum — specifically, the subcortical structures key to movement and thought, and among the first destroyed by Huntington’s disease. Once there, a solution of engineered viruses called AMT-130 is infused in a continuous trickle over roughly 12 hours. On an MRI monitor, the surgical team watches the liquid bloom through the brain in real time. 

All that — the catheter through functioning brain tissue, the hours-long neurosurgery, the viral solution — is just the delivery system. The real therapeutic payload is what that viral solution is carrying: a scrap of synthetic genetic material that promises, for the first time, a way to actually slow one of the most confounding neurological diseases. It also represents a proof of concept for gene therapy, an entirely different way of thinking about medicine. 

So what is gene therapy, exactly?   

Most conventional drugs are small molecules that circulate through the body and interfere with a protein or process that’s causing problems. Gene therapy works further upstream. Instead of dealing with the mess created by a faulty gene, it tries to intervene in the genetic instructions themselves, by delivering a healthy copy of a gene, silencing one that’s causing harm or, in more aggressive approaches, editing the DNA sequence directly, explains Rachel Harding, a molecular biologist and an assistant professor at the University of Toronto in the department of pharmacology and toxicology.

Huntington’s disease is an inherited neurodegenerative disorder caused by a mutation in a single gene. That mutation produces a toxic protein called huntingtin, which accumulates inside neurons and gradually kills them. The result is a crushing progression of symptoms — involuntary movements, trouble speaking and swallowing, cognitive impairment and psychiatric disturbances — that typically emerge in midlife and worsen over time. “There’s never a competition over which disease is the worst,” says Harding, whose work mapping the structure of huntingtin earned her the 2024 Nancy S. Wexler Young Investigator Prize. “But most neurologists agree that Huntington’s is one of the most devastating.”

Until recently, every existing treatment managed what Huntington’s does to a person, but nothing tackled the root cause or the underlying neurodegeneration. Then last fall, uniQure, a Dutch biotech company, released preliminary results from its AMT-130 trial. The therapy uses a viral vector to deliver DNA instructions into neurons, prompting cells to produce something called microRNA — basically, benign interlopers that piggyback on and interfere with the RNA molecules responsible for producing huntingtin.

Three years after treatment, patients showed a 75 percent deceleration in disease progression. Researchers also reported declines in a biomarker associated with neurodegeneration, which suggests the therapy may not just be masking symptoms but actually delaying the death of brain cells.

Wait — what’s a viral vector? Is that a virus?  

Basically, yes. The delivery problem is one of the central challenges in gene therapy. We can’t just inject DNA and RNA into the bloodstream and expect them to slip inside the right cells — our immune systems are designed to detect and destroy foreign genetic material. So scientists often repurpose modified viruses as delivery vehicles, exploiting their natural ability to weasel their way into cells and deposit genetic instructions. 

The most common are adeno-associated viruses, or AAVs, engineered to carry genetic cargo without causing disease. Different versions target different tissues. The AAV5 vector used in AMT-130, for instance, is particularly good at infecting neurons in the striatum. 

Why are we suddenly hearing so much about gene therapy?  

The idea for gene therapy has been around for decades: What if, instead of treating symptoms, doctors could fix disease at its genetic source? Early experiments in the 1980s and ’90s proved the concept was possible, including a landmark 1990 trial that treated a four-year-old girl born with a severe immune disorder. But the field was rocked in 1999, when 18-year-old Jesse Gelsinger, who had a rare metabolic liver condition, died after suffering a severe immune reaction during an experimental gene therapy trial. Research ground to a halt for years. 

Then came a series of breakthroughs. The completion of the Human Genome Project in 2003 gave scientists, for the first time, a full map of human DNA. Less than a decade later, researchers Jennifer Doudna and Emmanuelle Charpentier revealed the gene-editing capabilities of CRISPR-Cas9, a bacterial defense mechanism they showed could be reprogrammed to locate and cut specific sequences in any genome with unprecedented precision. Faster, cheaper and easier to use than earlier technologies, it transformed the field almost overnight, and won the pair the Nobel Prize in Chemistry in 2020. 

What kinds of diseases can be treated with this technology?  

According to Janet Rothberg, a senior director with the Toronto not-for-profit Centre for Commercialization of Regenerative Medicine, gene therapy is most powerful for diseases caused by a single identifiable mutation — one broken gene, one clean target. There are roughly 7,000 such diseases that affect more than 400 million people worldwide. These include inherited blood disorders such as sickle cell and hemophilia, as well as a range of neuromuscular, neurological and rare pediatric disorders, from immune deficiencies to various forms of vision and hearing loss.

Is gene therapy the same as cell therapy? 

“Not quite,” says Rothberg. “In gene therapy, we’re trying to deliver something that fixes the person’s own cells. In cell therapy, we’re actually giving them new cells.” Those cells, either modified or grown in a lab, are themselves the treatment. They’re meant to perform a job that can no longer be performed by the patient’s body.

CAR-T cancer therapy, for example, involves removing a patient’s immune cells, genetically engineering them to recognize cancer, and infusing them back into the body. That’s where the lines get blurry — many modern cell therapies also rely on genetic engineering. And both rely on genomics, the science of reading and mapping the genome, to identify their targets. 

Why does gene therapy cost so much?  

These therapies are extraordinarily expensive to produce, as each one is essentially handcrafted from biological material rather than synthesized in bulk. Manufacturing is heavily manual, R&D costs are enormous and patient populations for rare diseases are small, meaning costs can’t be spread across millions of prescriptions the way those for a common drug can. The first CRISPR-based gene therapy, a sickle cell treatment called Casgevy, costs U.S.$2.2 million per patient. 

CCRM, which operates OmniaBio, Canada’s largest cell and gene therapy manufacturing facility in Hamilton, Ontario, is actively working to automate the manufacturing process to help drive costs down. “The power of these therapies can’t be limited to certain people,” says Rothberg.

What role is Canada playing in all this?  

From research to manufacturing to clinical application, Canada has built a meaningful presence across the cell and gene therapy pipeline. Specific Biologics, a Toronto company spun out of Western University research, is focused on one of the central limitations of first-generation gene editing: many tools can effectively break genes, but are less good at repairing them precisely. Its platform, called Dualase, uses a two-cut editing system designed to remove and replace errant bits of code more accurately. In diseases caused by repeated stretches of faulty DNA, like Huntington’s, those paired cuts can excise the harmful repetitions entirely. “Gene-editing therapies that restore a genetic sequence precisely have been described as the ‘holy grail’ of gene therapies,” says Specific Biologics CEO Brent Stead.

Other Canadian companies are tackling different problems. Montreal-based Jenthera Therapeutics is developing a CRISPR platform that skips viral delivery systems entirely. The approach, which targets cancer, is designed with the aim of mitigating challenges related to both manufacturing complexity and adverse immune system responses in patients. Toronto’s Mediphage Bioceuticals, meanwhile, is working on synthetic DNA molecules that are easier to redose, a major hurdle with virus-based therapies, which typically can’t be readministered once the immune system recognizes the viral vector.

What happens next?  

AMT-130 hasn’t been approved yet, and the trial is small. But the implications may extend far beyond Huntington’s. If scientists can safely deliver genetic instructions deep into the brain and silence a disease-causing gene, the same platform could potentially be adapted for a range of neurological disorders, including ALS and Parkinson’s. Many of these conditions have been hard to treat because the underlying proteins can’t be reached by conventional drugs — either they’re too structurally elusive for traditional pharmaceuticals to latch onto, or they’re tucked behind the blood-brain barrier. Gene therapy offers a possible workaround by targeting the genetic instructions upstream instead. 

“It opens up the opportunity to drug the undruggable,” says Harding. “We could be in for an explosion of therapies, of new ways we can treat diseases.” 

The pharmaceutical industry is watching closely. Gene therapy has largely targeted rare diseases, but the tools that made AMT-130 possible are now being pointed at some of the most common conditions in medicine. 

In May, researchers published the preliminary results of a trial led by Verve Therapeutics, a biotech focused on applying gene editing to cardiovascular disease that was acquired last year by Eli Lilly for more than $1 billion. The study, published in The New England Journal of Medicine, showed that a single infusion of a gene-editing treatment reduced levels of LDL cholesterol — the bad kind — by as much as 62 per cent in patients with genetically high cholesterol, with effects that appear to persist over time.

Researchers hope the approach could eventually extend to anyone at risk of heart disease, which kills nearly 20 million people around the world each year. A one-and-done treatment for the leading cause of death globally would shift gene therapy from niche medicine to something much larger. nH 

Caitlyn Walsh Miller writes about technology for MaRS. Hospital News has partnered with MaRS to highlight Canadian innovations in health. 

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