Gene therapy helps rare disorders. Stories don’t always end well 2023

Gene therapies can save or change lives, give hope, and justify years of scientific research.

Clinical trials for unproven medicines often fail, especially for the first.

Alissa Feldborg’s tale is one.

The girl and her distraught parents had a chance to reverse her deadly prognosis at the University of Massachusetts T.H. Chan School of Medicine study.

Alissa, 3, died on Easter Monday, 28 months after gene therapy.

It was expected. When their 8-month-old daughter was diagnosed with Sandhoff disease, Thomas Feldborg and Daria Rokina were urged to prepare for her death.

Sandhoff, an ultra-rare hereditary illness, destroys brain and spinal cord nerve cells in healthy neonates. The youngster deteriorates quickly and dies by age 3.

The experiment, which USA TODAY published about in 2021 as part of a rare disease series, gave them a different future, even though the result wasn’t what they wanted.

“We are heartbroken, but also we realize within ourselves that the battle was lost long ago, not now,” Alissa’s father said in a video a week after her funeral. “It’s hard to say, but it was best for her in the end.”

See previously:Alissa’s sole hope was experimental gene therapy. Instead of death, she faces uncertainty.

Series continuation: New gene therapy could turn unusual diseases into “normal” lives.

Clinical trials promise

Feldborg and Rokina, who live in Copenhagen, Denmark, discovered about the UMass study online and were excited when Alissa qualified.

The researchers knew Alissa might not benefit—her condition may be too advanced, and the dosage, based on sheep studies, may be too low. They lost hope as the FDA took weeks and months to approve the medication.

Action brings hope, and the pair was glad for any glimmer.

At the end of January 2021, when Alissa was 13 months old, doctors delivered her two gene therapy dosages, one into her spinal cord and one into her brain.

It started well. She improved for six months. Smiled again. She appeared near.

“There were a lot of positive things after this treatment,” Rokina remarked.

Her swallowing and coughing improved, worrying her parents. The pair worried that the therapy might prolong Alissa’s vegetative state but not improve it.

“When we realized it wasn’t going to cure her, we were afraid that it would be a long devastating life for her,” Feldborg said.

How much? When?

18 months after Alissa’s treatment, the trial’s sponsor said it couldn’t afford to continue. UMass Chan raised cash to track nine dosed youngsters.

Dr. Terence Flotte, medical school dean, said via email that his team will try the therapy on one or two more children, increasing the total to 10 or 11.

The experiment included newborns and older children with later-onset illness. Flotte said the infants improved slightly and kept neurologic function longer following treatment, but other older children had mixed results.

Gene therapy, which helps children generate the enzyme they need, also works better in Tay-Sachs, a similar condition.

Series continuation:Fitz was born immuneless. His treatment may cure rare disorders.

Alissa was the initial patient. Later children received bigger doses and were treated earlier.

“They can stop the degeneration, but they cannot heal what is broken,” Feldborg remarked of scientists.

The pair regrets not convincing the FDA to be less cautious about the therapy. Feldborg and Rokina suggested a different outcome with earlier treatment and a higher dose. They would have risked cerebral hemorrhage for a better outcome.

“If we could have changed anything, we would have shouted loud enough for FDA to hear us.”

Progress requires risk.

Dr. Francis Collins, the longterm National Institutes of Health director and lifetime genetic research and therapy advocate, said medicine advances in fits and starts and relies on volunteers like Alissa’s family.

Collins stated, “I think it’s appropriate to be enormously inspired and excited about the potential” of gene therapy.

He stated DNA misspellings cause 6,500 uncommon diseases, but just 500 have cures.

Collins blamed biology for this therapy’s failure.

“People don’t appreciate how complicated human biology is,” said Collins, who has spent his career reversing progeria, a genetic illness that causes fast aging.

He claimed one or two spelling errors in a person’s 3-billion-letter genome can harm trillions of cells across the body, including the brain, which is difficult to treat.

“You can see the payoff,” Collins said of gene therapy like Alissa’s. “You just can’t see how long it is, how many twists and turns, how many unexpected hailstorms are going to hit you along the way.”

In an email, UMass’ Flotte noted it’s difficult for patients and families to get gene therapy first. “Those pioneering patients and families who choose to go first in such trials demonstrate great courage, as they make sacrifices for the benefit of those who come after them.”

Collins said gene therapy has great potential.

“I would want people to be optimistic that over the coming years we’re going to get much better at this—and not to feel hopeless, despondent or pessimistic,” he remarked.

Interpreting suffering

Alissa declined drastically in the last six months.

Seizures returned. Breathing was hard. Her parents believed she was suffering even though physicians said she wasn’t aware.

They were. Alissa’s 24/7 care dominated their lives and those of their four older children—three kids from his previous marriage and one from hers. “I would not wish this on my worst enemy,” Feldborg said.

Alissa was resuscitated five times in her final three weeks. Six times failed.

Feldborg and Rokina feel empty while the sons suffer in their own ways.

No feelings, no joy. “The sun is shining, spring is coming, but you’re indifferent,” Rokina observed.

Despite the trial’s disappointing end, they have no regrets.

Feldborg said Alissa bloomed briefly after therapy when she should have declined.

We hope her life has purpose. “The trial continues,” he stated. We hope it succeeds somewhere. If Alissa’s life has significance, then it does.”