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Earlier this month, the FDA approved an entirely new family of drugs, one so powerful that it could put CRISPR-based gene therapy to shame. Backed by two decades of research and a Nobel Prize, these drugs have the ability to cure inherited diseases—and do so without actually needing to edit the delicate genome.
The green-lit therapy is patisiran, a drug ten years in the making by the Cambridge-based Alnylam for genetic nerve damage. But in this rare case, the nature of the drug is perhaps more significant: patisiran is based on a technology called RNA interference, or RNAi, which allows doctors to silence genes that aren’t properly functioning.
Patisiran is just the tip of the iceberg. In theory, RNAi has the potential to cure any disease caused by “bad” proteins, such as stroke, Alzheimer’s, high cholesterol, or other neurodegenerative disorders. The potential is so grand that scientists have long dubbed the technology a way to “drug the undruggable.”
“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms,” said FDA commissioner Scott Gottlieb in a press release. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses.”
With other RNA-based therapies hurtling down the drug development pipeline, it’s likely we’ll be seeing more of these drugs soon. Here’s what you need to know. more
Gene therapy had a hell of a 2017. After decades of promises but failed deliveries, last year saw the field hitting a series of astonishing home runs.
The concept of gene therapy is elegant: like computer bugs, faulty letters in the human genome can be edited and replaced with healthy ones.
But despite early enthusiasm, the field has suffered one setback after another. At the turn of the century, the death of an 18-year-old patient with inherited liver disease after an experimental gene therapy treatment put the entire field into a deep freeze.
But no more. Last year marked the birth of gene therapy 2.0, in which the experimental dream finally became a clinical reality. Here’s how the tech grew into its explosive potential—and a sneak peek at what’s on the horizon for 2018.
1. Bad Blood, Meet CAR-T
It sounds like magic: you harvest a patient’s own immune cells, dose them with an injection of extra genetic material, and turn them into living cancer-hunting machines.
But in 2017, the FDA approved a double whammy of CAR-T immunotherapies. The first, green-lighted in August, helps kids and young adults battle an especially nasty form of leukemia called B-cell acute lymphoblastic leukemia. Two months later, a therapy for adults with non-Hodgkin lymphoma hit the scene.
Together, these approvals marked the long-anticipated debut of gene therapy in the US market. Previously, Europe has led the charge with its approval of Glybera in 2015, a gene therapy that reduces fatty acid buildup in the bloodstream.
The historic nod of confidence for CAR-T has already sparked widespread interest among academics and drug companies alike at finding new targets for the upgraded immune cells (the “T” in “CAR-T” stands for T-cell, a type of immune cell). CAR-T is especially exciting for the cancer field because it helps people who don’t respond to other classic treatments, such as chemotherapy.
But the technology’s potential is hardly limited to cancer. Last year, a preliminary study in two monkeys showed that genetically engineered stem cells can suppress and even eradicate HIV infections. The study, though small, tantalizingly suggests a whole new way to battle HIV after three decades of fruitless search for a vaccine. With multiple CAR-T therapies going through the pipeline, 2018 may very likely welcome new members onto the gene therapy scene.
The Future of Cancer Treatment Is Personalized and Collaborative
In an interview at Singularity University’s Exponential Medicine in San Diego, Richard Wender, chief cancer control officer at the American Cancer Society, discussed how technology has changed cancer care and treatment in recent years.
Just a few years ago, microscopes were the primary tool used in cancer diagnoses, but we’ve come a long way since.
“We still look at a microscope, we still look at what organ the cancer started in,” Wender said. “But increasingly we’re looking at the molecular signature. It’s not just the genomics, and it’s not just the genes. It’s also the cellular environment around that cancer. We’re now targeting our therapies to the mutations that are found in that particular cancer.”
Cancer treatments in the past have been largely reactionary, but they don’t need to be. Most cancer is genetic, which means that treatment can be preventative. This is one reason why newer cancer treatment techniques are searching for actionable targets in the specific gene before the cancer develops.
When asked how artificial intelligence and machine learning technologies are reshaping clinical trials, Wender acknowledged that how clinical trials have been run in the past won’t work moving forward.
“Our traditional ways of learning about cancer were by finding a particular cancer type and conducting a long clinical trial that took a number of years enrolling patients from around the country. That is not how we’re going to learn to treat individual patients in the future.”
Instead, Wender emphasized the need for gathering as much data as possible, and from as many individual patients as possible. This data should encompass clinical, pathological, and molecular data and should be gathered from a patient all the way through their final outcome. “Literally every person becomes a clinical trial of one,” Wender said.
For the best cancer treatment and diagnostics, Wender says the answer is to make the process collaborative by pulling in resources from organizations and companies that are both established and emerging.
The issue arises in how the Cas9 proteins researchers use are manufactured.
The authors of the study noted that the most widely-used versions of the protein are extracted from the bacteria Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). In bioengineering, particular bacteria—usually selected for being widely available and easy to cultivate—are often used to synthesize particular proteins. For example, most of our medical insulin is made from genetically modified E. coli. The researchers behind the study questioned whether because S. aureus and S. pyogenes regularly infect humans we might have built up some resistance to their proteins already. The infections they cause, often called strep and staph, are widespread enough that most people can be expected to have been exposed to the bacteria.
The study discovered that in many cases, human immune systems produced T-cells that specifically responded to the Cas9 protein from Staphylococcus aureus. This suggests that attempts at therapeutic use would cause an adaptive immune response that might render the therapy ineffective. Indeed, the authors of the paper wrote that use of these proteins in those who’ve been exposed to this bacteria could be harmful. “It may even result in significant toxicity to patients,” according to Stanford University’s Matthew Porteus, a senior author of the paper. A paper by Wei Leong Chew suggests, “If left unchecked…it could lead to mortality.”
The authors of the paper wanted to ensure immune issues weren’t overlooked. “Like any new technology, you want to identify potential problems and engineer solutions for them,” according to Porteus. “And I think that’s where we’re at. This is an issue that should be addressed.”