Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) belongs to a family of disorders more commonly known as Batten disease, although it would be an overstatement to say that Batten disease is known at all. It only occurs in about two to four in every 100,000 births in the United States. Its effects, however, are devastating.
In people with CLN2, an aggressive form of Batten disease that first presents around age 2 to 4, a faulty gene inhibits the production of a crucial enzyme that allows brain cells to get rid of waste. The resulting accumulation leads to widespread cell death. Symptoms are mild at first, but progress rapidly, leading to loss of motor skills, hearing, vision, and eventually death.
For Jennifer and Tracy VanHoutan’s young son, Noah, it all started with small, quiet changes. A slight tremor. A speech delay.
Doctors told them not to worry, it was probably a temporary condition. But his problems got worse. He had unprovoked falls and convulsions. They took their then three-year-old son to see some of the best neurologists in the country.
Then they received the call that would change the course of their lives.
?[The doctor] asked me to get a pen and paper,? said Jennifer VanHoutan, speaking to BTN Impact the World in 2011. “He said all these long words to me. It was very confusing to me at first. Then Tracy came into the room and looked for her on Google And it wasn’t good.
Noah had CLN2. Because Batten disease is an inherited condition, they should have their infant daughters, twins Emily and Laine, tested. Their devastation was compounded when they learned that Laine also had CLN2, although she had not yet shown any symptoms.
Their days were soon taken up with caring for their children. That alone would be enough for most people. But for Jennifer and Tracy, who graduated from the University of Iowa, it marked the start of a journey to eradicate Batten disease.
David Sleat and Peter Lobel, professors at Rutgers University, have studied lysosomal storage disorders like Batten disease for years. In 1997, the pair made a breakthrough with CLN2, identifying the gene defect that caused the disease.
“This discovery arose from our fundamental cell biology studies of the lysosome, a part of the cell responsible for breaking down molecules such as proteins, sugars and fats.” Sleat said via email.
In 2009, the VanHutans launched Noah’s Hope, a non-profit organization dedicated to their mission to raise awareness and fund research around Batten disease. In the years since Noah and Laine’s diagnoses, Tracy has become a tireless advocate for people with Batten disease.
At WORLDSymposium 2010, a scientific conference dedicated to lysosomal storage diseases, Tracy met Dr. Sleat. A few months later, he and Laine visited Sleat and Lobel’s lab. While Tracy and the researchers discussed their findings, Laine played on the floor with her princess dolls.
“I don’t think Peter and David really had the chance to meet a lot of children affected by the disease,” he added. Tracy said. “I think it was very impactful for them. We’re just blessed to have these guys.
After identifying the cause of Batten’s disease, Lobel and Sleat set out to design a treatment that would fight CLN2 at its root.
“Once we identified the cause of the disease, we started thinking about different ways to treat it,” he added. said Sleat. “We have developed methods to produce tripeptidyl peptidase 1 (TTP1), the missing protein in LINCL.
A genetically modified mouse was their first test subject. Breakthrough Enzyme Replacement Therapy (ERT) worked, halting the progression of the disease by allowing brain cells to properly break down their waste products. Lobel and Sleat received a patent for their therapy which was licensed to BioMarin, a California-based pharmaceutical company specializing in ERTs.
Work has begun to bring the therapy to market. But, as is often the case with all drug trials and especially those for rare diseases, the approval process is slow and arduous – smaller than normal sample populations can mean trial delays. years or even decades.
But the CLN2 approval process got a huge boost from Tracy VanHoutan.
?When [BioMarin] was ready to go into clinical trial, they filed the application both in Europe and at the FDA, ? Tracy said. “It was approved immediately in Europe, but the FDA wanted to wait for additional data. Me being me, I started finding ways to pressure the FDA. I spoke at a congressional panel on rare diseases on the problem of exporting clinical trials. I sat on a panel at the FDA and talked about all the terrible things going on with these kids.
BioMarin got fast-track approval for the therapy they call Brineura. Although they will have to continue to study the effects of the drug, its presence on the market means that it can now be used to treat children who desperately need it. And the results so far appear to be nothing short of a miracle, as children treated with Brineura have seen an almost complete halt in CLN2 progression.
“If you look at children with Batten disease, their progression can normally be traced, age over ability, as a steep downward line.” Tracy noted. ?The minute a child went on [Brineura] this line went straight across, if not backed up a bit. It far exceeded anything I had ever hoped for.?
With Brineura now on the market, the VanHutans and Noah’s Hope continue to work on behalf of people with NCL disorders. They are currently funding projects that range from repurposing lipid-lowering drugs for use as a possible co-therapy for Batten disease to creating a colony of genetically modified pigs for use in CLN2 studies.
Sleat and Lobel also continue to work toward ever better therapies for NCL disorders. In addition to refining TTP1 and the method of delivery of the synthetic enzyme, they are investigating biochemical ways to accurately track disease progression and response to treatment. The hope is that this will help both future clinical trials and enable personalized treatment for individual CLN2 patients.
