In drug discovery for rare diseases, gene therapies are beginning to show clinical promise. Will the strategy pay off? A report from a Charles River symposium

Gene therapy, the use and manipulation of disease to treat or prevent disease, has had its ups and downs. When researchers began experimenting with it in the 1980s and 1990s, many thought it would transform medicine. But it became steeped in controversy after an 18-year-old named Jesse Geisinger, who suffered from a genetic liver disease, died during a gene therapy trial in 1991 at the University of Pennsylvania. His death, attributed to the recombinant adenoviral vector shuttling the corrective gene, brought other trials to an abrupt halt.

But technologies have since evolved sufficiently to make the strategy more viable. In 2013, Dutch biotech uniQure received approval from European regulators to market Glybera, a gene therapy product for lipoprotein lipase deficiency, a rare genetic defect that prevents people from properly digesting fats. And Spark Therapeutics says it is readying to submit an application to the US Food and Drug Administration for its gene therapy product voretigene neparvovec, a one-time treatment for an inherited retinal disease that causes blindness in children.

At a rare disease symposium on Monday that was sponsored by Charles River Guangping Gao, Professor and Director of the Gene Therapy and Vector Core at the University of Massachusetts Medical School, described how his group is using recombinant human adeno associated viruses (AAVs) to try and cure Canavan’s disease, a fatal condition triggered by a mutated version of a gene called ASPA passed on by both parents. The dysfunctional gene prevents the clearing of N-acetyl aspartic acid from the brain, and as the acid builds up it begins eating away at the myelin that insulates our brain neurons, turning it into a spongy mess.

In 2001, researchers from the Jefferson Medical School drilled six holes into the skull of a 6-year-old girl with Canavan’s and infused millions of recombinant AAV particles into her brain in hopes that it would start expressing the normal gene. The treatment was determined to be safe, but it didn’t work.

Gao’s lab is also using AAV as a viral vector but he’s settled on a different variant—AA9—which is better than other AAV vectors in crossing the blood-brain barrier, he says. This has made it possible to introduce the gene therapy intravenously rather than infuse it directly into the brain. The treatment achieved early, complete, and sustained rescue of the lethal disease phenotype in CD mice, said Gao, and more recently was tested in a young boy on a compassionate use basis. The child tolerated the therapy but Gao said it is too early to tell whether it will also be effective.

Despite the promise of gene therapy, finding investment partners is hard. Gao said a full-fledged clinical trial to test the efficacy of this gene therapy cost tens of millions of dollars. Finding willing partners to invest in a trial that only benefits a small number of children is extremely difficult.

Huntington’s disease

Gene therapy strategies are also a ripe area of exploration in the Huntington’s disease (HD) space, says Douglas Macdonald, the director of research operations and alliances at CHDI, a disease foundation committed to finding therapies that slow the progression of this devastating and ultimately fata movement disorder. Macdonald, who gave the keynote address as the symposium, said several AAV-based strategies designed to lower expression of the Huntingtin (HTT) gene, which is linked to HD, are being explored as a potential therapeutic strategy. And the first clinical study, a Phase 1 safety trial of anti-sense oligonucleotides (ASOs)—which are designed to reduce (silence) HTT—got underway last year. It remains to be seen, however, whether this treatment—which worked well in animal models—also is effective in humans.

Still, while gene therapies are emerging as a viable strategy for treating many of these rare diseases, which often arise from a single gene mutation that, in theory at least, should be fixable with today’s tools, gene therapy treatments that are both safe and effective will take years to develop. Many patients don’t have that much time.

Ryan’s story

Mark Dant, whose son, Ryan was born with a lysosomal storage disease known as MPS1 (for mucopolysaccharidosis 1), is a case in point. A mutation in a gene prevents the production of an enzyme needed to break down certain byproducts of chemical reactions, causing this lethal disease that appears in early childhood. With no treatments available to help their son, Dant and his wife, Jeanne embarked on a relentless global to find a way forward for Ryan. This remarkable story had a happy ending. A California scientist who’s MPS research the Dant Family foundation funded, developed an enzyme replacement therapy that ultimately turned Ryan’s death sentence into a chronic but manageable condition. Periodic infusions of the ERT, delivered first intravenously and later on directly into the spine, have allowed Ryan to have a normal life. He graduated this year from the University of Louisville and his father said he would like to pursue a job in sports.  The ER therapy is available in countries across the globe.

Dant, who was greeted at Monday’s symposium with a standing ovation, said curing these disease is a great goal, but disease modulators are just as important. Had we waited for a gene therapy, Dant said, our son would not have survived.

For more on rare diseases, here’s a brief summary of a 2016 Charles River Symposium on rare diseases.