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Genetic Linkage

Medical Success Stories: From Cystic Fibrosis to Diabetes

The many guises of CF.
A skinny little boy, with mocha skin and curly black hair, lived in the apartment building next door when I was growing up in Brooklyn in the 1960s. He didn’t live long enough to go to kindergarten. He had cystic fibrosis.

Today’s tots with CF face a far brighter future. A recent report in the Annals of Internal Medicine applied trends in survival from 2000 to 2010 to project life expectancy for children diagnosed in 2010: 37 years for girls and 40 years for boys. (The difference may reflect hormones or the extra creatinine in the more muscular male of the species.) Factoring in the current rate of treatment improvements gives a soaring median survival of 54 years for women and 58 years for men when those kids grow up!

That's great news, although some younger people with severe disease will still contribute to the lower end of the survival curve. (See my write-up in Medscape Medical News and a recent post on the history of CF at my DNA Science blog.

THE CFF PATIENT REGISTRY
The Cystic Fibrosis Foundation Patient Registry began in 1966, when my young neighbor died. It's followed 26,000 of the nearly 35,000 individuals with CF in the U.S., with 5,000 added over the past decade as treatments have expanded and people with milder symptoms added.

In the early days, deaths were more often due to malnutrition than to the impaired respiration for which the disease is best known.

Success has come from diverse realms.

First came high-calorie diets, digestive enzymes mixed into applesauce, and airway clearance exercises, eventually helped with devices such as vibrating vests. Then came a parade of drugs: antibiotics, mucolytics, and more recently Kalydeco to refold misfolded CFTR (CF transmembrane conductance regulator) protein, a drug so effective that it’s Facebook page is called Kalydeco Miracles. And treatments start sooner in life thanks to universal newborn screening (since 2009) and prenatal carrier testing.

IS CF MORE THAN ONE DISEASE?
The definition of CF continues to evolve as more mutation combinations are identified and their phenotypes described. It has never made sense to me that different mutations in the CFTR gene all produce what we call cystic fibrosis, yet different mutations in the beta globin gene cause different clinical entities. Hemoglobin C and sickle cell disease even affect the same amino acid position. The situation in naming single-gene diseases seems a little like how lumpers and splitters see biological classification.

But that may be changing. A recent report in PLOS Genetics suggests that CF is two diseases, defined by whether or not the lungs are affected. At least nine variants of CFTR spare the lungs, but cause male infertility, pancreatitis, or sinusitis -- in some men, all three.

"Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids. When that doesn't happen, the acids cause the inflammation, cyst formation and scarring of severe pancreatitis. Bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function," explains co-author David C. Whitcomb, MD, PhD and chief of gastroenterology, hepatology and nutrition at the University of Pittsburgh School of Medicine. In times past, CF wasn’t part of the differential diagnosis for men with pancreatitis, chronic sinusitis and infertility, but with working lungs.

“I know one MD who got through med school a severe asthmatic, now diagnosed with CF. We are diagnosing people better at all ages, and newborns are being screened, which contribute to increase in life expectancy,” says Paul Quinton, PhD, a professor of biomedical sciences at the University of California, Riverside, School of Medicine and medical advisor to Cystic Fibrosis Research Inc.. He has CF.

Tracking the natural history of a disease, which patient registries makes possible, is crucial in determining whether a new treatment works. Another recent DNA Science post addressed the issue of whether boys with Duchenne muscular dystrophy who walked farther on a treadmill in a set time after receiving an experimental genetic treatment had really improved, or if their strides were within the range of normal for the disease.

Natural history studies reveal aspects of disease that could be important in developing treatments. For CF, the registry revealed a period of increased risk during adolescence. Until age 10, annual mortality is below 0.5%, but it jumps during the teen years to 3-4% before plateauing at age 25. An editorial accompanying the Annals of Internal Medicine paper suggests suggests that the tendency of teens to not eat so well and forego treatments and therapies, and increased susceptibility to pathogens such as Pseudomonas aeruginosa and MRSA, might explain the vulnerability.

SURVIVORS OF CHILDHOOD DISEASES
How will the health care system embrace a population of adults with CF?
While the editorialists claim “caring for adults with CF requires a village,” Lisa Tuchman MD, MPH, an adolescent medicine specialist at Children’s National Medical Center, is more positive. “We‘re seeing a trend across all pediatric-onset health conditions. For CF there has been a lot of thoughtful planning and careful analysis, mostly facilitated by the registry.” Dr. Tuchman and Michael Schwartz, MD, from the Pediatric Pulmonary Medicine & Cystic Fibrosis Center, Lehigh Valley Health Network, recently published a study in Pediatrics Pediatrics about successful transition to adult care for people with CF.

I asked Dr. Tuchman whether there are precedents for extended-survival patient populations.

“Lots! Over 90% of little kids who get cancer are going to survive, so the system has responded by creating centers for adult survivors of childhood cancers. We see this in sickle cell disease, adult programs because people are living longer with it. And a lot of babies born with HIV disease are now young adults transferred to adult health care systems. It is across the board: metabolic diseases, hemophilia, diabetes. There’s a growing population of adults with pediatric-onset conditions,” she said.

GENE THERAPY
A brute-force attack on symptoms, coupled with a targeted molecular approach, has tamed cystic fibrosis. Although news reports describe Kalydeco as correcting CF at its source, the source of inherited disease is not the protein, but the gene that encodes it. And that’s where gene therapy comes in. It, too, has had recent spectacular successes.

My book The Forever Fix: Gene Therapy and the Boy Who Saved It", chronicles development of gene therapy for Leber congenital amaurosis type 2, which has given vision to more than 200 people, many of them children. Other blinding conditions aren’t far behind.

At the American Society of Gene and Cell Therapy annual meeting last May, I heard similar stories, most notably for adenosine deaminase deficiency and severe combined immune deficiency (SCID) X1. Said Adrian Thrasher, MD, PhD, from Great Ormond Street Hospital for Children of ADA deficiency, “We expect to cure a majority of these kids today if they can have a bone marrow transplant, but if they can’t …” and he then launched into the details of ongoing clinical trials for gene therapy. It works, saving children who would otherwise die in infancy. ADA deficiency, like CF, is no longer a “life-shortening inherited disease.”

And the list will grow, especially as "traditional" gene therapy of supplying working genes shares successes with genome editing techniques that actually replace or fix faulty genes.

GASTRIC BYPASS AND DIABETES
Although I know double-blinded, controlled clinical trials are the best way to demonstrate efficacy of a new therapeutic approach, the most compelling example for me was watching my daughter Heather following her gastric bypass surgery last May.

Her type 2 diabetes vanished, in just 4 days.

I’d read the reports of gastric bypass surgery curing diabetes. And Heather’s physician had told me that more than 90% of the bypass patients with diabetes at Albany Medical Center no longer had the disease. The hypothesized mechanisms make sense: dampened secretion of ghrelin, the stomach’s hunger hormone; or forcing glucose out of the bloodstream into the rerouted small intestine to provide energy to digest food that’s a bit chunkier than normal.

Heather’s surgery had been delayed two months because she couldn’t get her A1C down – the 3-month measure of blood glucose. She went from one to two to three oral diabetes drugs, with exercise and a very low carb diet. I even invented a low glycemic index soup/stew that helped a little.

But only insulin worked. Looking ahead to a lifetime of treating diabetes is what pushed Heather to have the surgery.

Someday, gastric bypass surgery could be a front-line treatment for type 2 diabetes, even among people of normal weight. In terms of both economics and quality of life, it makes sense. Or perhaps we’ll find a way to less-invasively recreate the altered microbiome of an ex-diabetic after weight loss surgery.

Let's hope that cystic fibrosis, Leber congenital amaurosis, and type 2 diabetes are only the beginning of a trend towards tackling disease, in a multitude of ways.

(This post originally appeared at
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