[Editor's note: This is the first of a three-part series looking at detours and advances in gene-based medicine.]
The genetics of Margaret Benson's lungs don't match anything else in her body, which is why she is still breathing. Margaret had a double lung transplant. Her first pair of lungs were choked and scarred by cystic fibrosis and seven years ago they quit.
Cystic fibrosis (CF) is a genetic disease that hits the lungs the hardest. Respiratory failure is the primary cause of death. When the gene responsible was found in 1989, "suddenly there was hope," recalls Margaret. "For the families coming up, what an incredible gift for them, that maybe in their children's lifetime a cure will be found". The focus of all that hope rested on gene therapy.
Gene therapy is being developed for cancer, heart disease, and many of other conditions based on genetics. But to use the word "therapy" to describe it is a bit premature. To date there is only one clinical application that is truly a gene therapy. It is a treatment for a type of throat cancer that has only been approved for use in China.
There is no gene therapy approved for cystic fibrosis, and there is no cure even though the disease was thought to be an ideal candidate for one. The high hopes for gene therapy that peaked in the 1990s have dwindled. Developing gene therapy that works is much harder than people thought, and the story of the struggle for a cystic fibrosis gene therapy illustrates why.
What is gene therapy?
"Gene therapy is using genetic material to correct a disease or to reverse the clinical course of a disease," explains Dr. Jim Hu, a senior scientist and one of the top cystic fibrosis researchers in Canada who specializes in gene therapy at Sick Children's Hospital in Toronto.
Genetic material, usually DNA, directs the construction of everything biological. In genetic disease, changes in genetic material result in shoddy construction or sometimes no construction at all.
Gene therapy can fix genetic disease by providing directions that build biological machinery that works. This is done by putting normal copies of the gene into cells, repairing malfunctioning genes, or changing the activity of genes by getting them to work harder or work less.
If it works, gene therapy would have a big advantage over drugs because it can fix everything at once. One gene has many different functions. "We don't know which of those functions it would be the most important to mimic," explains Dr. Eric Alton, head of the UK Cystic Fibrosis Gene Therapy Consortium. "The only way to be certain of replicating the normal function is to put in a normal copy of the gene, which would therefore replicate all of the different functions."
How cystic fibrosis kills
Cystic fibrosis is caused by mutations in a single gene, which makes it a bit of an oddity. Most diseases with a large genetic component have many different genes that are involved, which makes figuring them out even more difficult. Since CF has only one gene involved, it was thought to be a prime candidate for gene therapy.
The gene found was the cystic fibrosis transmembrane conductance regulator gene (CFTR). When CFTR works properly, it makes a structure in the cell that moves chloride particles in and out. Although it doesn't sound like a very big job, chloride particles have an electrical charge. How they enter and leave the cell changes electrical signals that regulate many cellular functions.
In cystic fibrosis, a chloride traffic jam causes the cells that line most of our inner workings to produce mucus that is too thick and clogs things up. This can lead to dire consequences in the lungs.
The thick mucus produced in cystic fibrosis doesn't move well. Airways get blocked up and infections are a constant problem because bacteria trapped by the mucus are not removed. Constant inflammation and damage to the lung eventually results in respiratory failure.
In the digestive system, tubes that pipe in digestive juices to the intestine can get clogged. This causes people with CF to not digest their food well, which can lead to diabetes and osteoporosis. Even reproductive tubes can be blocked up, which leads to infertility in men.
Everyone has two copies of CFTR, and you can have one mutated copy of the gene and still be healthy. However, when two people with only one working CFTR gene have children, there is a one in four chance that the child will have both of their CFTR genes mutated and be born with cystic fibrosis.
"They said at the time it will be within five years that a cure will be found, that's what I remember hearing," says Margaret, remembering the excitement in the cystic fibrosis community back in 1989. As the years passed by and children died, Margaret remembers how the hope and elation in the CF community "slowly trickled down to, when are they going to find it?"
There were plenty of people, families and doctors, who wanted a cure fast. One year after the genetic discovery, the CFTR mutation was successfully fixed in cells grown in a lab. Based on that work, Dr. Robert Beall, the vice president and medical director of the Cystic Fibrosis Foundation, predicted that there would be a gene therapy cure for CF within the decade.
Dr. Barbara Nakielna is one of Margaret's doctors and the head of the cystic fibrosis adult clinic at St. Paul's Hospital in Vancouver. She remembers hearing Dr. Beall's prediction at a cystic fibrosis conference in the early 1990's. "I was excited," recalls Dr. Nakielna, "maybe not quite as confident as Robert Beall was, but certainly optimistic."
Now, many years later, Dr. Nakielna's optimism has run out.
"I certainly won't throw my hands up and say it's a hopeless cause, but I don't think that in this particular disease that it's necessarily the right way to go because we've been at it for long enough".
"We knew it wasn't going to be five years," recalls Dr. Johanna Rommens, one of the geneticists that was part of the Toronto team that discovered the gene for cystic fibrosis. "We had found a gene that nobody had every studied before, we didn't know what it did."
Knowing the gene doesn't tell you how to fix anything, it just tells you where to start. First you have to figure out how the normal gene works and how the mutations change things. Then there is a large web of biological processes that domino off from that change.
The first clinical trials used modified viruses to deliver the normal CFTR gene since viruses have machinery designed to get genetic material into cells. The body and engine of the virus stayed the same, but the genetics were altered so that they didn't hijack the cell and replicate like viruses normally do. Most of the viral genes were also taken out and switched with the normal CFTR gene. But all the early gene therapy trials failed, the biology was much more complicated than anticipated.
"Initially people didn't anticipate all the problems," says Dr. Hu. "All the early clinical trials were doomed to fail."
The first obstacle was mucus. Even in a normal lung, getting past the mucus to the cells that need the gene is difficult. But the residual viral genes that were included with the CFTR to help with delivery caused the most problems. Even if they were there to help, the body still recognized them as viral and attacked. The machinery needed for gene delivery was shut down and more inflammation flared up in addition to the damaging inflammation that cystic fibrosis already caused.
In the end, the amounts of normal CFTR gene getting in and working were not enough to make a difference. Non-viral delivery systems have also been tried that bypass most of the inflammation issues caused by viral shuttles, but have still not worked effectively in humans.
However science advances with failure as well as success. Even though the progress since the gene discovery in 1989 might be perceived as slow, some would say that everything is well on schedule.
"We're well on course and well on time for the normal production of moving from bench to bedside," says Dr. Alton. His group, the UK Cystic Fibrosis Gene Therapy Consortium, has been working on optimising gene therapy for cystic fibrosis since 2001.
Dr. Alton points out that in the pharmaceutical industry, the normal development of a drug from start to final product usually takes 20 years, and gene therapy is newer and more involved.
"It's a difficult thing to do to put a gene into a lung cell," says Alton. "Evolution has designed the lung to keep things out and we're trying to work against evolution."
The consortium has been focusing on optimising current non-viral gene delivery methods. Soon they will start a large clinical trial with a gene delivery system that carries genes in microscopic capsules built from the building blocks of fat molecules (see tomorrow's article).
However, getting the normal CFTR genes into the cells that are constantly dying and being replaced is not very efficient. The therapy would have to be given repeatedly, and that may not always be feasible, as was the case with the first viral shuttles that caused inflammation.
"What you really need is the baby cells, or the stem cells," says Dr. Rommens.
Stem cells are the ideal target for gene therapy. They are easier to put genes into and the effect would be longer because they don't die off, they make more cells. But the research on stem cells is in its infancy. How to get enough stem cells for a therapy, or get them into the lung to repair it, are still not worked out.
The slower than hoped for progress of a gene therapy cure for cystic fibrosis offers some lessons for why similar cures for other diseases have yet to materialize. Scientists have learned that getting a genetic treatment to cells that need it is much more difficult than figuring out a genetic fix to a single gene disease. In other words, gene therapy is much easier in theory than in practise.
But research in gene therapy delivery systems is progressing rapidly, and once it gets sorted out, medicine will final have the engine it needs to move us into the genetic revolution that was promised.
None of the current gene therapies in development for cystic fibrosis would help Margaret since her new lungs are free of CF. But she still struggles with problems in her other organs and the anti-rejection drugs she takes because of the transplant.
Even though she still lives with cystic fibrosis, and has to be very mindful of her health, Margaret doesn't look or act sick. The girl that the doctors didn't think would see 20, now a very active 48-year-old and fiercely proud of her age.
"I'll stand on the rooftops and tell people how old I am, especially for the kids coming up," says Margaret. With or without gene therapy, there is hope. More and more people with cystic fibrosis are living well into adulthood, "and that's what kids need to hear."
Tomorrow: A new way to deliver gene medicine to tumours?