By the time Toby Willis arrived at Children's Hospital Los Angeles in March 2018 to receive a first-of-its-kind gene therapy treatment, he had lost most of his eyesight to the inherited eye disease retinitis pigmentosa. Willis, 44, a software engineer for Expedia in Seattle, could only see shapes and shadows. He'd given up driving 20 years earlier, and while he could get along on foot with a cane and his seeing-eye dog, his remaining eyesight was deteriorating.

Then Willis learned from a geneticist that his disease was caused by a rare mutation in the gene RPE65 and that it could be treated with a new gene therapy surgically delivered into each eye. The therapy, called Luxturna, involves inserting a functional copy of RPE65 that takes over for the faulty gene, producing a protein vital for proper vision. While he wouldn't regain all his sight, doctors told him he might recoup enough to significantly improve his quality of life. He signed up right away for the new therapy at Children's Hospital LA – one of the first hospitals equipped to provide it.

"Almost immediately, everything appeared brighter. I could see a lot more contrast, lines and edges, and moving cars on the street," Willis says. The unwelcome bright flashes caused by his disease were greatly reduced, and his ability to navigate his surroundings in the dark improved. "I still need my dog to be safe, but the change has been dramatic for me."

Luxturna is one of just three gene therapies on the market, all of which were approved in 2017. It was a banner year for a technology that was nearly abandoned in 1999, after teenager Jesse Gelsinger died of an immune response during a clinical trial of a gene therapy to treat his rare metabolic disorder. But a handful of bold scientists stuck with the technology, fine-tuning methods of inserting healthy genes into the body to ideally correct diseases without causing toxic side effects. Their work led to Luxturna, as well as Kymriah to treat leukemia and Yescarta for lymphoma.

There is still a risk of side effects: Some patients have experienced high fevers, confusion and other reactions, some life-threatening, to the cancer gene therapies, plus a loss of white blood cells, which must be replaced with regular plasma infusions. Luxturna has caused eye infections, increased eye pressure and retinal changes. The products are also pricey – Luxturna has a list price of $425,000 per eye, and the other two are similarly expensive. But many insurers are covering the treatments, recognizing the potential to cure patients with one-time procedures.

Those three products have ushered in a new age. Dozens of academic research centers and biotech companies are working intensely on gene therapies to treat many more cancer types, as well as a range of more common disorders, from heart failure and diabetes to Alzheimer's disease. Some of the therapies, like the two new blood-cancer treatments, entail removing immune cells from patients, modifying the cells' genes so the body can recognize and attack disease, and then reinjecting the cells into the bloodstream, unleashing a targeted assault. Others involve inserting a copy of a healthy gene that can take over vital functions from a faulty gene – the method by which Luxturna works.

There are some 1,200 human trials of gene therapies in progress worldwide. And pioneers in the field say this is only version 1.0 of a technology that could improve the outlook for millions of patients. "Genetic engineering is amazing. Soon we'll be able to hard-wire cells so they are smart enough to make sophisticated decisions," singling out diseased tissues for destruction but leaving healthy organs alone, for example, says Carl June, professor of immunotherapy at the University of Pennsylvania Perelman School of Medicine and an inventor of Kymriah.

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Replacing Wayward Genes

At least 50 of the trials underway address diseases of the eye – an organ that's particularly well-suited to the technology. More than a dozen eye diseases can be blamed on bad genes that are inherited, including macular degeneration, a leading cause of blindness in people 50 and older. Plus the eye is a small organ that doesn't launch an overly aggressive immune system response to foreign invaders. That's important, because new genes are introduced into the body using viruses that have been engineered to spread their therapeutic payloads in patients without themselves causing illness. The most popular family of viruses used for gene therapy, so-called adeno-associated viruses, initially raised the risk of immune responses like the one Gelsinger suffered. But they have been engineered over the last decade so that sort of reaction is less of a threat and to make them better at transporting good genes into precise locations.

In the case of Luxturna, the virus containing the therapeutic gene is placed in the retina, where the gene stays put, acting as a stunt double of sorts by pumping out a protein that a healthy RPE65 gene would normally make. A different treatment, called RGX-314, is now being developed to treat wet age-related macular degeneration. It uses an inserted piece of DNA that allows cells to continuously produce a therapeutic protein that stops blood vessels in the back of the eye from leaking – the cause of progressive blindness.

Although medicines that stop the leakage can themselves be injected directly into the eye many times a year, some ophthalmologists believe that setting the ongoing process in motion through gene therapy will ultimately be a better option for many patients. "It's not that much different from, say, a cataract surgery. We numb the eye, it's a painless procedure, and the patient goes home that day," says Jeffrey Heier, co-president and medical director at Ophthalmic Consultants of Boston, one of the sites conducting a phase one clinical trial of RGX-314. The therapy's developers have early evidence that a single insertion of the gene results in continuous production of the therapeutic protein.

The idea of introducing therapeutic genes into the body is taking off in the treatment of blood disorders, too, including sickle cell disease, a hereditary condition that causes abnormal production of the oxygen-transporting protein hemoglobin. Scientists are testing a method of inserting a new gene that makes normal hemoglobin into stem cells taken from the blood of patients with the disorder. Then the cells are infused back into patients in hopes that the newly introduced gene will produce enough healthy hemoglobin to prevent the misshapen, or "sickled," cells from causing the inflammation, anemia and organ damage that are hallmarks of the disease.

Julie Kanter, associate professor at the Medical University of South Carolina, has treated a handful of sickle cell patients in an early stage trial of the therapy, called LentiGlobin, one of whom was cured, she says. Although the trial is designed for adults, Kanter envisions a day when the gene therapy will be performed in children with sickle cell disease, sparing them years of pain and life-threatening organ injuries. There is no effective treatment for the disease, and though it can be cured with a bone marrow transplant, fewer than 10 percent of patients are able to find a matching bone marrow donor. Gene therapy, she says, "could be transformative."

LentiGlobin is also in human trials to treat a severe form of beta thalassemia, which causes a chronic shortage of red blood cells and has only been treatable with frequent blood transfusions to date. During a recent trial of LentiGlobin in 13 patients, 12 were able to stop receiving the transfusions altogether.

Toby Willis still relies on his guide dog Dazzler but calls changes to his vision "dramatic." (Jovelle Tamayo for USN&WR)

Wielding 'Molecular Scissors'

Other researchers are working with an emerging gene-editing technology known as CRISPR-Cas9. This technique, which could enter early-stage human clinical trials in the U.S. relatively soon, involves cutting out problematic DNA sequences with Cas9, an enzyme often described as molecular scissors, thus creating a changed sequence at the break and often inserting new genetic material.

Scientists at CRISPR Therapeutics in Cambridge, Massachusetts, are using CRISPR to edit blood-forming stem cells so they continuously produce fetal hemoglobin – a protein that prevents symptoms of sickle cell but that the body normally stops producing in childhood. Similar techniques are now being developed to treat hemophilia, cystic fibrosis, HIV, severe combined immunodeficiency, or SCID, and more, says Matthew Porteus, a scientific co-founder of CRISPR Therapeutics and associate professor of pediatrics at Stanford University School of Medicine.

Gene editing isn't free of controversy. Some critics worry that the potential to edit out so-called germline mutations – genetic abnormalities in sperm, eggs or embryos – could theoretically result in changed traits being passed to future generations and could be used to delete undesirable but non-life-threatening traits like short stature. And in June 2018, the CRISPR world was shaken by two scientific studies reporting that some CRISPR-edited cells could spark the growth of cancerous tumors.

Still, the recent successes have inspired other scientists to target some of the most prevalent diseases. A team at the Icahn School of Medicine at Mount Sinai in New York is planning a 2019 trial of a therapy that will introduce a gene into the coronary arteries that produces a calcium-regulating protein essential for improving heart function in patients with chronic heart failure. And scientists at Seattle Children's Research Institute are investigating the possibility of using CRISPR-Cas9 to introduce a gene that would halt the immune process that destroys insulin-producing cells in the pancreas, potentially providing a permanent solution for Type 1 diabetes.

A New Tack in Cancer Treatment

At age 11, Rachel Elliott survived a bout of acute lymphoblastic leukemia, or ALL, but seven years later, in 2015, her disease relapsed, and side effects from chemotherapy landed her in a medically induced coma for a month. When she relapsed again in 2016, she had few options for a cure. That is, until Elliott was accepted into a clinical trial of the gene therapy developed by Penn's Carl June.

Kymriah is a chimeric antigen receptor T cell, nicknamed CAR-T – a gene therapy made from immune cells taken directly from patients. The genes of the cells are altered in a lab so they recognize and target CD19, a protein marker that's prevalent on certain leukemia and lymphoma cells. Then the T cells are grown and infused back into patients, where they track down and kill leukemia cells. The treatment was approved in 2017 based on remarkable results from the pivotal clinical trial: 83 percent of patients with ALL who received the treatment went into remission within three months.

CAR-T treatments are now being developed to treat other blood cancers, including multiple myeloma, as well as solid tumors like glioblastoma, a deadly form of brain cancer. One major challenge is that many cancers either lack a clear marker like CD19, or they share markers with vital organs in the body, making it difficult to develop CAR-Ts that will kill cancer but leave healthy tissues alone. June and others are working to engineer gene therapies that will enable the creation of CAR-Ts that are smart enough to distinguish cancer cells from normal ones.

"If a cancer cell has targets A, B and C, but the heart also has A, the CAR-T will only kill the cancer and it will spare your heart," June says. Penn scientists are now recruiting people with multiple myeloma, melanoma and one form of bone cancer into the first human trial in this country to test CRISPR-Cas9. They plan to use the DNA-snipping technique on the CAR-T cells in the lab to insert genes that will make them even better at pursuing their targets.

For now, the first generation of engineered T cells is already making a difference for patients like Elliott. She received two infusions of gene-altered T cells in December of 2016, after which her cancer disappeared. Now 21, she's studying at Virginia Commonwealth University School of Business, with dreams of working in the health care industry. "I hope to be part of making this therapy readily available to many more patients," Elliott says. "I truly believe gene therapy will become the pillar of all cancer treatments."