Scalpel, stethoscope, antibiotics--as each landmark tool earned its place in the physician's bag, it brought a leap forward in patient care. Perhaps today's most anticipated new tools are those growing out of the mapping of the human genome.
With the eagerness of a family road trip, it has been difficult not to keep asking "are we there yet?" "Soon" is the answer we keep hearing, and now that we are 15 years down the road on a long journey, perhaps it's time to look and see how far we've come.
"We're seeing some remarkable successes in gene therapies and in genetic information advancing other forms of treatment. Right now we're at the very beginning of directly using gene editing to correct disorders in humans," Neil Lamb PhD, faculty investigator for HudsonAlpha Institute for Biotechnology, said. "The field is only around five years old, and most of that time the work has been on human cells in the lab. Last November, the zinc fingers nucleases gene technique was used to treat a patient with Hunter's Syndrome. Other patients have been treated since then, and the early results have been promising,"
CRISPR Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) is the gene editing technique that has been grabbing most of the headlines over the past few years, but Lamb said there have been advances in a range of gene editing tools that can be selected to fit the nature of the targeted gene and the objective.
"We see a lot of work in blood disorders. A clinical trial is gearing up to test CRISPR gene-edited therapy for treating patients with ß-thalassemia and sickle cell anemia," Lamb said. "CRISPR is also being used to modify iPS cells in stem cell therapy. In animal models, CRISPR modifications allow us to study what is going on in diseases. We can look at a mouse with the same mutation as the patient and see how it responds. A report just came out showing proof of concept for correcting a muscular dystrophy mutation in a dog."
So far, researchers are focusing on disorders caused by a single gene mutation. Tools with the capabilities to address diseases involving multiple genes are still beyond the horizon.
Refining and improving gene editing tools, including CRISPR, are a current focus of research.
"There were some reports showing that earlier forms of CRISPR may be a bit too permissive and could have some off-target effects. Newer versions are more specific, and we're also seeing a more compact form that can be used to do different things," Lamb said.
Whereas gene therapy is often used to add a gene, gene editing can be used to remove a mutation or replace it with a corrected version. The compact version of CRISPR allows space for more carrying capacity of chemicals like methyl groups and it uses CRISPR's ability to recognize specific sequences to guide the chemical where it is needed to turn the volume of a protein's production up or down, depending on whether more or less is needed.
Gene therapies already approved by the FDA include an injectible treatment for a form of hereditary blindness.
"Over the past four years, this treatment for an RPE65 mutation has helped blind patients regain some sight so they can see shapes, shades and colors. It is an expensive treatment that can only be done on one eye at a time, but it is a first step toward restoring sight in people with genetic blindness," Lamb said.
Oncology is an area at the forefront of precision medicine, using genetics to identify specific types of cancer cells and any vulnerability that might make specific therapies more effective. Genetic tools are also being used to harness the power of immunotherapy and to make the patient's cancer more detectable to improve the ability of the body's own defenses to fight it. In chimeric antigen receptor (CAR T) cell therapy, cells from patients are modified and re-inserted back into the patient to help the immune system recognize and fight cancer cells. The FDA has approved two CAR T cell therapies in humans. One is for treating children with acute lymphoblastic leukemia (ALL) and the other for adults with advanced lymphomas.
Researchers are also working on better ways to deliver genetic treatment to different areas of the body. This also includes work in small molecules capable of crossing the blood brain barrier to treat conditions in the brain.
Looking down the road, Lamb believes we will see an increasing number of gene therapies targeted to more disorders.
"Gene editing will be crossing over into mainstream medicine," he said. "But the most powerful thing we have learned from the work that has grown out of sequencing the genome is a better understanding of how diseases develop. Knowing more about what is happening opens the door to developing more effective treatments to help our patients."