Beyond three-parent babies: New drugs offer hope for mitochondrial disease
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Women with mitochondrial disease could soon have a way to avoid passing their harmful genetic mutations on to their children, after the US Institute of Medicine — the country’s premier medical advisory group — last week endorsed an experimental technique to create embryos with DNA from three parents.

But while that might help the next generation, it doesn’t offer a remedy for the 30,000 or so Americans living with inherited defects in their mitochondria, which are often called the power plants of the cell because they fuel the body’s energy needs.

A new wave of experimental drugs aims to change that by reversing the debilitating fatigue, muscle weakness, neurological problems, and myriad other health issues that have come to define daily life for this desperate patient population.

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“They have no quality of life. They’re so tired. Some are in bed all day along,” said Dr. Amel Karaa, an internist and clinical geneticist at Massachusetts General Hospital, who is helping to lead trials of some of these new therapeutic candidates. “We’re very hopeful that within the next five to 10 years, we’ll have at least one new drug on the market” specifically approved for treating mitochondrial disease.

Current treatments for the estimated 1 in 5,000 children born each year with defects in their mitochondria amount to little more than exercise regimes and concoctions of vitamins and supplements that help mop up some of the toxic byproducts of a broken mitochondrial system.

These “mito cocktails” can cost up to $1,000 per month, have little standardization, and only deal with patient symptoms. The next generation of therapies now in clinical testing, experts hope, will combat the core energy problems at the heart of these disorders.

“We are very, very excited that really, in 2016, for the first time, we can say there are multiple clinical trials happening around the world for people with primary mitochondrial disorders,” said Cristy Balcells, the mother of an 11-year-old with a mitochondrial disease and executive director of MitoAction, a patient advocacy group.

“To be told, ‘The best we can offer you is to take some high-dose vitamins,’ is not enough,” said Balcells, who lives in the Boston area.

One of the leading drug contenders is Bendavia. This small peptide agent from Stealth BioTherapeutics binds to a component in the inner shell that surrounds the mitochondria, stabilizing the target, protecting it from damage, and helping to recharge the cellular powerhouse and improve energy output.

“It allows mitochondria to repair themselves,” said the drug’s discoverer, Dr. Hazel Szeto, a pharmacologist at Weill Cornell Medicine who founded Stealth 10 years ago. “It becomes like a regenerative medicine.”

Reata Pharmaceuticals is taking a different approach: It’s trying to boost the production of mitochondria in the cell to make up for their poor energy output.

These new mitochondria still carry genetic defects and “each one unit might be suboptimal,” said Dr. Marni Falk, director of the Mitochondrial-Genetic Disease Clinic at the Children’s Hospital of Philadelphia. “But if you make more, they might collectively make sufficient energy to meet the needs of the cell.”

Reata’s drug is now being tested in a 56-person, placebo-controlled study at sites across the United States and Denmark. Falk, a trial investigator, enrolled her first patient last week.

Two other companies — Edison Pharmaceuticals and Raptor Pharmaceuticals — are each also advancing clinical-stage drugs designed to boost levels of a toxin-fighting molecule called glutathione, a powerful antioxidant that is deficient in patients with various mitochondrial diseases.

If they pan out, all these experimental agents could help protect the body from the noxious effects of wayward mitochondria, but none ultimately contends with the underlying genetic flaws.

To do that requires a special kind of “gene therapy,” in which working copies of a mutated gene are introduced into the DNA.

This is technically challenging and fraught with safety issues for most mitochondrial diseases, which manifest themselves throughout the body.

But one mitochondria-linked disorder in particular — Leber hereditary optic neuropathy, or LHON — is a promising target for gene therapy because the main symptoms, such as blurry vision, are limited to the eye. (Vision-related disorders are ideal candidates for gene therapies because physicians can deliver DNA fixes through targeted ocular injections, and then extract the eyeball if anything goes awry.)

Last month, the French company GenSight Biologics launched two Phase 3 gene therapy trials for LHON patients who had recently started to lose their vision.

“Hopefully, in this trial we’ll be able to prevent visual loss if we treat people early enough in the process,” said trial investigator Dr. Mark Moster, a neuro-ophthalmologist at the Wills Eye Hospital in Philadelphia, who expects to enroll his first patient within the next few weeks.

All this clinical research activity is “incredibly exciting and invigorating to our patient community,” said Phil Yeske, the science and alliance officer for the United Mitochondrial Disease Foundation.

Mitochondrial replacement via three-parent babies could ultimately benefit “a slice of a slice of a slice of the affected community,” Yeske said — namely, women with mutated mitochondrial DNA who want to have genetically related children.

These new therapies coming down the pike, by contrast, offer hope for everyone with mitochondrial disease — including for children like Jacob Hallberg.

Jacob Hallberg, 10, and his mother, Maria Hopfgarten.
Mary Elizabeth GraffMaria Hopfgarten credits an experimental drug with improving her 10-year-old son Jacob Hallberg’s communication skills and immune system.

The 10-year-old started taking the Edison drug in late 2012 for a rare mitochondrial disease that primarily affects the brain. His mother, Maria Hopfgarten, credits the experimental agent for dramatically improving Jacob’s communication skills and immune system, although he continues to suffer from seizures and the fallouts of poor muscle tone.

Speaking on the phone this week from the emergency room in Children’s Hospital Colorado, where Jacob was awaiting scans for a bowel obstruction, Hopfgarten couldn’t help but wonder what her son’s life might have been like if the drug had been available earlier. And she worried that the slow pace of drug development might not bring these new therapies to market fast enough for the legions of people with mitochondrial disease who need them.

“The hope is there,” she said, “but the question is: ‘Will our kids still be around when these drugs are finally FDA-approved?’”

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