Gene therapy’s time seems to have come

Once considered too risky, now offering hope to patients long without it

By Carolyn Y. Johnson | Source: The Boston Globe

Two boys born with a fatally flawed gene that leaves them defenseless against common infections have returned to their homes in Argentina and Chile after receiving an experimental gene therapy at Boston Children’s Hospital.

Untreated, babies with their “bubble boy” disease would die in infancy, but in 2010 and 2012, doctors inserted good copies of the gene into their bone marrow cells, restoring the boys’ immune systems. Both are now well into toddlerhood.


Kirsti Pigney is participating in a trial for gene therapy to treat blindness. She can’t tell whether the therapy is working, but said her vision hasn’t worsened.

Meanwhile, Kirsti Pigney, a 76-year-old from Taunton who woke up one day unable to see, is participating in a safety trial of a gene therapy being tested by Cambridge-based Genzyme for a form of blindness. She recently had a virus, modified to carry a therapeutic gene, injected into one of her eyes.

Years after it was hyped, then vilified after the death of a teenager, then mostly forgotten by the general public, gene therapy has rebounded, and hospitals, companies, and investors in the Boston area have jumpedon the bandwagon. Patients are enrolling in a growing number of clinical trials here, and in some cases showing dramatic improvement. The technique, in which doctors “infect” patients’ cells with viruses engineered to carry useful genes, has matured and evolved.

It is a future few could have predicted a decade ago. Once trumpeted as a possible panacea for diseases ranging from sickle cell anemia to cystic fibrosis, gene therapy faced serious questions after the high-profile death of an Arizona teenager in a clinical trial in 1999. The case seized national attention, led to inquiries into failures of regulatory oversight, and scared away many investors. But some researchers continued to work to overcome the safety and technical hurdles.

“When I first went to UMass, several prominent scientists said, ‘What do you mean, gene therapy? They tried that and it didn’t work,’ ” said Dr. Terence Flotte, the dean of UMass Medical School, who has been working in the field since the late 1980s.

Over the years, scientists have improved the safety of the viruses used to insert good copies of genes into cells. Cautiously, they began to test the technique in people again. In 2008, two groups of researchers reported restoring some vision in people with a rare retinal disease. The next year, eight out of 10 children with bubble boy disease were cured in a European trial.

Scientists reported in 2010 that a French man with a genetic blood disorder no longer needed monthly transfusions after being treated by a gene therapy made by Cambridge-based Bluebird Bio.

Pigney and her husband Keith thoroughly researched the procedure when her doctor mentioned the Genzyme trial. Instead of replacing a defective gene, the treatment inserts a gene directing eye cells to produce a protein that inhibits the abnormal growth of blood vessels — the reason for her vision loss.

Undaunted by gene therapy’s checkered history, the couple was intrigued by recent promising results. Pigney had always enjoyed sewing and crocheting, and now can do those things only if her husband threads the needle. She can’t write or drive a car or read small print.

“I tend to be a little bit optimistic, and I dreamed about my eyesight coming back. I never felt afraid of the injection,” Pigney said. “They’ve given me so many now. I’m like a pincushion.”

She can’t tell whether the therapy is working, but said her vision hasn’t gotten worse. At this point, the trial is testing only the safety and dosage.

With a handful of experimental trials open or in the works at local hospitals, gene therapy seems to have found its footing.

Dr. David Williams, director of translational research at Boston Children’s Hospital, said he plans this summer to bring together key players from area hospitals to share the expertise Children’s has gained from launching trials. The trials include one for a rare, genetic immune system disease called Wiskott-Aldrich syndrome and another scheduled to begin this summer for the neurodegenerative disease adrenoleukodystrophy, best known from the role it played in the movie “Lorenzo’s Oil.”

UMass Medical School has several active trials for patients with a genetic flaw that leads to lung and liver disease; the most advanced trial one has treated eight patients. They have also treated two patients, including Pigney, with age-related macular degeneration. At scientific meetings, Flotte, the UMass dean, said he’s begun to notice something he hadn’t seen before: lots of interest from the business community — including drug companies and investors — eyeing a hot field.

Bluebird Bio went public earlier this month, raising $101 million. The first gene therapy, Glybera, made by the Dutch company uniQure, was approved in Europe last year, for a rare disease that causes fat to build up in the bloodstream. A spokesman for the company said it had requested a meeting with the US Food and Drug Administration to get clarity on the approval process.

As the technology has matured, the understanding of its possible uses has also expanded as scientists have learned more about basic biological mechanisms. UMass Medical School biologist Craig Mello’s co-discovery of a way to turn off genes won him a share of a Nobel Prize in 2006 — and it introduced the possibility that gene therapy could be used not just to introduce good copies of genes, but to shut down malfunctioning ones.

Dr. Robert Brown, a professor of neurology at UMass who studies ALS, said that the ability to do more than just add good genes has ignited broader interest in the technique.

“Many of these diseases have a need for silencing” a gene, Brown said. “In Huntington’s, some forms of Parkinson’s, and most forms of familial ALS, the real challenge is not loss of [gene] function, but how to respond” to mutated genes that are producing proteins that harm the body.

Animal testing in primates or other large animals set to begin this year are beginning to change the discussion about the potential for using gene therapy in those neurodegenerative diseases.

“I’ve been doing this for many years starting in the early 1980s, and we’re now at a point where we’re talking about when we would treat the patient,” said Dr. Neil Aronin, a professor of medicine and cell biology at UMass who has long studied Huntington’s. “We didn’t even have that discussion before.”


Takeaways from the Rare Disease & Orphan Drug Leadership Congress

Takeaways from the Rare Disease & Orphan Drug Leadership Congress

I was tweeting fast and furiously at the 7th Annual Rare Disease and Orphan Drug Leadership Congress on July 18 and 19 in Philadelphia, and here are some of the insights I captured. Stephanie Okey from Genzyme did an excellent job moderating and set the tone by starting off the conference saying, “No disease is too rare to deserve treatment.”

For me, the highlight of these events is getting to meet rare disease advocates in person, and I captured a few on video. One panel of patient advocates included Dean Suhr of the MLD Foundation and the RARE Project, Kim Ryan of Fight Colorectal Cancer and Jill Panetta, PhD, of the Polycystic Kidney Disease Foundation. The topic was “How to Interact with Advocacy Groups to Facilitate Access.” This was a key theme that resonated throughout the two days: in the orphan drug space, it is essential for pharmaceutical companies to engage with patient advocacy groups. This echoes what we’ve learned at Siren in our more than ten years of working in the space.

Patients are impatiently waiting
The patient advocate panel agreed that it’s essential in the orphan drug space for biopharma companies to proactively communicate with advocates. Ryan noted that the earlier the better that advocacy groups are involved in the clinical trial process. Even in rare diseases a lack of awareness and understanding can be a barrier to clinical trial participation. As a result, advocacy groups are taking a much more active role in supporting clinical trial education.

Dr. Panetta explained that the current patient-led demand for treatment is driven by pipeline transparency, the rise of empowered patients and social media. She said that rare disease patients are closely following the advances in basic research and “patients are impatiently waiting for treatments.”

Focus on the patient
In his presentation Roger Garceau, MD, from NPS Pharma, made it clear that his company takes a patient-centric approach. He declared that when rare disease advocacy groups exist they are very influential and can be a valuable partner for pharmaceutical companies. He noted that access is not just providing drug, but that companies have to provide “burden-free product access.”

Other high points included Emil Kakkis, MD, PhD, presenting the work that he is doing with the EveryLife Foundation for Rare Diseases and Marc Boutin from the National Health Council discussing how the MODDERN (Modernizing Our Drug and Diagnostics Evaluation and Regulatory Networks) Cures Act addresses current barriers. Elizabeth Ottinger, PhD, from the National Institutes of Health, described the progress of the Therapeutics for Rare & Neglected Diseases (TRND) program. Since 2009 there have been 14 projects with two drugs currently in Phase I, as well as one natural history study. She announced that the program will soon be accepting applications for new projects.

I left the conference feeling both inspired and overwhelmed—inspired that great progress is being made and a little overwhelmed by the many challenges ahead.

By Eileen O’Brien, Director of Search & Innovation at Siren Interactive

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