Sanfilippo syndrome A is a neurodegenerative condition caused by a genetic error in metabolism: because of a missing enzyme, long-chained sugar molecules cannot be broken down. Toxic substrates accumulate in cells, causing a rapid cognitive decline and, later, motor decline. Most affected children die in their teens or earlier.
There is no treatment, and when Karen Aiach’s daughter Ornella was diagnosed with Sanfilippo syndrome A, no companies were even working on the disease.
As a mother, Aiach could not accept that.
In 2009, she left her financial career to co-found her own biotech company in her native France. With Aiach as CEO, Lysogene has raised $30 million, according to the Boston Business Journal. The company is poised to conduct its second clinical treatment trial for Sanfilippo syndrome.
But back in 2005, when Ornella was a baby, Aiach was overcome with hopelessness. “You’re just suffocating, you’re overwhelmed by the feeling of unfairness, you feel like you’re in a bottle,” she said in a keynote last week at Harvard Medical School’s conference Precision Medicine 2016: Rogue Therapeutics.
Correcting the Sanfilippo defect
As Ornella got older, she lost her language skills. It took most of Aiach’s energy to manage Ornella’s hyperactivity and compulsive behavior. Things were breaking in the house. And Ornella barely slept. “This disease is absolutely exhausting for the child and family,” says Aiach.
Aiach began gathering information on Sanfilippo syndrome A (also known as mucopolysaccharidosis type IIIA or MPS III), joining a growing cadre of citizen scientists.
“My unique purpose was to try to put together a program to find a cure for that disease, no matter what the clinicians said,” she recounted. “Because I was not a scientist, I could ask any question I wanted.”
She learned that Ornella had a genetic mutation causing a deficiency of the enzyme sulfamidase. Could the enzyme somehow be replaced?
Aiaich was introduced to Olivier Danos, PhD, now senior vice president of gene therapy at Biogen Idec. Danos co-founded Lysogene with Aiach in 2009 and remains its senior scientific advisor.
Because of the difficulty of getting effective drugs across the blood-brain barrier, Danos proposed introducing a gene therapy vector into the brain. The working gene would be taken up by neural cells and “act as an enzyme factory,” Aiach said.
But the fledgling company selected a vector that showed all signs of being safe.
From 2008 to 2010, Lysogene sponsored preclinical studies in mice at the University of Adelaide in Australia, using the adenovirus AAVrh10 to deliver the sulfamidase gene, SGSH, and a companion factor, SUMF1. The treatment restored enzyme activity in the mice and reduced accumulation of toxins in their cells.
Clinical fast track
In 2010, Lysogene received orphan designation for its product, LYS-SAF-302, in the European Union. In 2011, a clinical Phase I/II trial was approved in France and the first four patients were treated, including Ornella.
The treatment entailed a two-hour operation to inject the gene therapy vector directly into the brain through a series of small holes in the skull. “We have to be willing to consider very innovative approaches, even a neurosurgical one,” said Aiach.
All four patients weathered the treatment safely and showed possible moderate improvement in behavior, attention and sleep. Three of the four, including Ornella, were over age 5 when treated; the ideal would be to treat children much earlier, Aiach said.
Still, at age 11, Ornella is calmer, less hyperactive and more expressive. A four-year follow-up study continues to track the children.
Lysogene is preparing to launch a 20-patient Phase II/III study in 2017, using a refined vector. In late 2015, LYS-SAF-302 received orphan drug designation and rare pediatric disease designation from the FDA, making it eligible for priority review.
The company recently opened an office in Cambridge, Mass., and has launched a natural history study of Sanfilippo syndrome. It has also branched into other disorders, including GM1 gangliosidosis, a Tay-Sachs-like disease, in collaboration with the University of Massachusetts Medical School and Auburn University in Alabama.
Lysogene’s goal now is to become the premier gene therapy company for central nervous system disorders, bringing together small biotechs focused on rare diseases and large, well-resourced pharmaceutical companies.
“You have to have a strong focus,” Aiach advised other would-be parent entrepreneurs. “It’s important to be very curious, never to be shy and to ask the questions that you need to ask.”