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Genetic Linkage

As Blindness Gene Therapy Nears the FDA Finish Line, A Shout-Out to Activist Families

On a spectacular September Sunday in 2008, 8-year-old Corey Haas, using his cane and holding his mother’s hand, stepped tentatively forward on the pathway leading into the Philadelphia zoo. Hearing kids yelling about the giant balloon hanging above the zoo, he looked up – and screamed. It was the first time he’d seen the sun. Corey was headed toward certain blindness when he’d had gene therapy at Children’s Hospital of Philadelphia, just days earlier.

So begins the talk I’ve given many times since publication of my book, "The Forever Fix: Gene Therapy and the Boy Who Saved It.

Last Thursday, I was glued to my laptop, watching and listening to physicians, researchers, family, and patients present their cases for FDA approval of
Luxturna (voretigene neparvovec), the gene therapy that Corey, now a high school senior, received. He and dozens of others participating in several clinical trials can now see, thanks to the gene therapy for RPE65-mediated inherited retinal dystrophy. The treatment introduces functioning genes into the thin layer of pigmented cells that hugs the rods and cones – one time.

Not far behind gene therapy for the blindness is Lenti-D, to halt progression of cerebral adrenoleukodystrophy (ALD), aka Lorenzo’s oil disease. An "interim analysis" published last week in STOP ALD Foundation. It started with Michaela and Augusto Odone’s invention of Lorenzo’s Oil to help their son, setting the example that so many families have since followed in raising the funds and finding the researchers to develop and deploy gene-based treatments. But the Odone’s inspiration went back even farther, to an observant mother in Norway.

PKU: A Clue in Urine

In 1931, Borgny Egeland noticed a strong musty odor to her young son Dag’s urine. He and his sister Liv were beginning to show signs of intellectual and physical disability. The father mentioned the oddly scented urine to a friend, who told a friend, Asbjörn Fölling, who was a doctor interested in biochemistry. Dr. Fölling analyzed the urine in a lab at the University of Oslo, with Borgny hauling over buckets of the stinky stuff.

By 1934 Dr. Folling had pinpointed a missing enzyme causing accumulation of the amino acid phenylalanine, an inborn error of metabolism later named phenylketonuria, or PKU. He then identified it among hundreds of people languishing in mental institutions. Could a low-protein diet counter the biochemical build-up?

German physician Hörst Bickel came up with the first PKU diet in 1954, and today children start on a more refined “medical food” as soon as they are diagnosed following newborn screening test, which began in 1963. PKU was the first such test.

Hold that thought.

Lorenzo Odone was born on May 29, 1978, to Augusto, an economist with the World Bank, and Michaela, a linguist. In the summer of 1983, Augusto was sent to the Comorros Islands, off the southeastern coast of Africa, and Michaela and Lorenzo came along. "Lorenzo learned French in the Comorros and some Comorrian words. He was a very gifted, precocious child" who loved classical music and Greek mythology, Augusto told me (he died in 2013).

The boy was healthy and active in the Comorros, but problems began shortly after the family returned to the United States and he started kindergarten. Lorenzo began to have difficulty paying attention. The usually calm child would fly into rages. He fell at Christmastime, and by the spring was falling so often that it was clear he couldn’t see. Lorenzo suffered blackouts and memory loss, seizures, had difficulty speaking, and was very tired.

The diagnostic odyssey began. Lorenzo didn’t have a brain tumor, seizure disorder, Lyme disease, or ADHD. But then telltale white areas on his brain MRI indicated ALD. The protective layers of fatty myelin around his brain neurons were melting away. His aggression, spawned by frustration at losing skills, would escalate until he gave up and withdrew from the world. Lorenzo would die by age eight, predicted the experts, because it was too late for a bone marrow transplant.

ALD affects one in every 18,000 to 21,000 newborn boys (the gene is on the X chromosome), so it wasn’t surprising that the Odones hadn’t heard of it. They got to work right away, huddling over biochemistry, molecular biology, and genetics journals and textbooks at the NIH library in Bethesda. They learned that Lorenzo’s symptoms arose from build up of "very long chain fatty acids" -- VLCFAs – in the brain, adrenal glands, skin, and blood.

Deep within Lorenzo’s cells, proteins that formed porthole-like openings in tiny sacs called peroxisomes weren’t there, due to a mutation in a gene called ABCD1. The damaged portholes kept out the enzyme that breaks down the VLCFAs. Normally the fats would be cut up and repackaged with other fats and some proteins to make myelin, the insulation on brain neurons that enables them to transmit messages.

Myelin isn’t directly slathered onto a neuron like mustard on a hot dog, but instead fills cells called neuroglia that encase neurons like bubble wrap. Deflating the bubble wrap shuts down neurons, and because the recipe for myelin is so complex, several such "demyelinating" conditions exist. Multiple sclerosis is the most familiar.

The type of glia affected in ALD come from bone marrow via the bloodstream, and that’s what makes the gene therapy described two weeks ago possible.

Most long-chained fatty acids indeed come from the diet, but it wasn’t as simple as restricting one nutrient, as was the case for PKU. And that had already been tried for ALD, unsuccessfully. Then in 1986 a paper described a work-around, oleic acid, which sops up the enzyme needed to make the fatty acids that build up. The Odones figured out what to do, found a biochemist in England to do it, and Lorenzo’s Oil was born. It contained fatty acids from canola, olive, and mustard seed oils.

Ann and Hugo Moser at the Kennedy Krieger Institute refined the diet. Augusto Odone went on to co-write the 1992 film Lorenzo’s Oil, and star Susan Sarandon took Michaela to the Academy Awards. Augusto told me that the film was about 80% true, 20% Hollywood. Hugo Moser praised the film as an excellent work of fiction, saying that it exaggerated clinical trial results and invented conflicts between parents and doctors. What offended many familiar with the disease was the cheery ending of kids taking the oil looking much too healthy.

Lorenzo likely lived well beyond age 8 because of incredible care, including round-the-clock nurses and a pool extending from the living room where his limbs were exercised. But still he required diapers, tube feeding, and frequent suctioning of saliva. When Michaela died in 2002 of cancer, a family friend took over her tireless care of Lorenzo. On May 30, 2008, Lorenzo choked and then bled to death – possibly because of the blood-thinning effects of the oil – before a rescue squad could arrive. It was the day after his thirtieth birthday.

Did the oil extend Lorenzo’s life? Even Augusto had doubts. But what the story of its invention did was to inspire families to not give up, and to tackle the daunting science themselves. So I’ll end with a shout out to three of the family-run not-for-profits I’ve written about with exciting events:

My Heroes

Laura King Edwards gave a TEDx talk, Running Towards Rare, about her sister Taylor’s battle with Batten disease in Charlotte on October 13.

Cure CMT4J is holding the Dare to be Rare gala on October 20 in Newburyport MA. I wrote about the Duff family, and Talia’s battle with this ultra-rare form of Charcot-Marie-Tooth disease, for Rare Disease Day 2017.

Max Randell (two-time gene therapy recipient) turns 20 this month, and Canavan Research Illinois
is honoring him October 21 at the 19th Annual Canavan Charity Ball in Chicago. I wrote about him here.

I covered the historic FDA meeting October 12 that approved the licensing of the first gene therapy for a single-gene disease, RPE65 mutation-associated retinal dystrophy, Corey's disease, for Medscape Medical News and will post patients’ testimony here next week. Let 2018 be the year of gene therapy!

(This post first appeared at my DNA Science blog for Public Library of Science.)

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