There are no drugs that stop the progression of Huntington’s disease, a rare and fatal genetic condition that afflicts about 30,000 people in the United States. Ditto for Parkinson’s disease, affecting about a million people in this country, and Alzheimer’s disease, now seen in 5 million people in the U.S. and on a massive upswing.
Current drugs for these neurodegenerative diseases, which can help to reduce some symptoms, work by tweaking the signaling that occurs between neurons. “The problem with those therapies is that as the brain ages the neurons become more and more unhealthy, so this approach is like trying to optimize the running of a broken machine through greasing parts, but what is really necessary is replacement or restoration of the broken components,” says Katharine Sepp, chief executive officer and co-founder of Oxalys Pharmaceuticals. “What you want to do is create a healthier brain overall.”
Oxalys aims to do just that, using an advanced cell-culture platform developed at MIT for finding compounds that slow or stop the advance of neurodegeneration.
The Toronto-based company has received an orphan drug designation from the U.S. Food and Drug Administration (FDA) for a drug candidate for Huntington’s disease, and expects to launch a clinical trial for its drug within two years.
“There’s a tremendous unmet medical need for Huntington’s disease,” Sepp points out. “Huntington’s is a complex neurological disorder that involves psychiatric changes, cognitive decline and changes in motor coordination. There’s only one FDA-approved drug, which lessens motor symptoms but does nothing to improve the cognitive decline or the psychiatric changes. Patients really struggle. It’s very devastating. We need to find something that will treat the disease in an acceptable way.”
Models of Degeneration Scientists have made major progress in understanding the genetic mechanisms that drive diseases of the aging brain such as Huntington’s, but creating in vitro models of the conditions for testing drug candidates has been challenging.
Oxalys co-founder Joost Schulte developed a very different cell-culture technique, which expresses a high proportion of the human Huntington’s disease gene within Drosophila fruit-fly neurons.
One earlier “cell-free” method of drug discovery searched for compounds that could break up the aggregations of disease proteins that appear in the brain cells of people with these conditions. However, the compounds these studies identified often were toxic to cells, and there’s an ongoing scientific debate about the roles the aggregates play in the disease. Another approach created neurons that could grow indefinitely in culture, but it didn’t reflect the normal aging process in neurons.
Working in the lab of Troy Littleton, MIT professor of biology, at the Picower Institute for Learning and Memory, Sepp and Oxalys co-founder Joost Schulte developed a very different cell-culture technique, which expresses a high proportion of the human Huntington’s disease gene within Drosophila fruit-fly neurons.
In these cultures, “you can tell clear differences between the freshly prepared neurons expressing the human disease gene versus neurons that don’t carry the human disease gene,” Sepp says. Neurons that express the human disease gene display axons and dendrites that are shorter and more likely to branch, as well as aggregations of the disease protein.
These starkly visible differences between healthy and diseased cells allowed the neuroscientists to create a highly robust assay for screening compounds that help keep the cells healthy.
Moreover, the assay was an excellent candidate for volume screening of drug candidates. The scientists could image the live cells by a robotic microscope, and then analyze them with advanced image-analysis software to find these changes in structure in an automated and unbiased way. “It takes a lot of the labor out of the work, so we could upscale our platform to screening tens or hundreds of thousands of compounds,” Sepp says.
In a first round of volume screening of chemical compounds, the researchers found four compounds that turned the diseased cells back into normal cells, Sepp says. The compounds also worked well in a fruit-fly model of the disease.
“We wanted to screen many more compounds because we saw how robust the assay was, but the facility we were using was more suited to running smaller drug libraries,” she says. “So that really got us thinking about starting a company.”
Platform Payback Sepp and Schulte originally envisioned a startup that would offer the screening platform itself. But biotech and business experts in the MIT Enterprise Forum suggested that the platform’s benefits could be demonstrated best by a drug that succeeded in clinical trials.
Following this path, Oxalys is a “virtual company” with the two founders as the only full-time employees. “We will keep it small for the next few years, because as you commercialize a drug it goes very quickly through various stages of drug development that require diverse expertise,” Sepp explains. “The most efficient model is outsourcing, where you bring in consultants and contract research organizations who specialize in these various components as you move along.”
As the startup broadens its funding, Oxalys also looks for backers with expertise. The most suitable venture or pharmaceutical partners will have teams that are experienced in pharmaceutical development, ideally in neurology and more ideally in neurodegeneration, she says.
Moving ahead with pre-clinical development, last year Oxalys achieved the key step of the FDA approval for orphan drug designation for its lead Huntington’s disease therapeutic.
The orphan drug designation brought access to research grants, tax credits for clinical trials and other incentives aimed to smooth the path into clinical studies. Given the rigor of the FDA process, the approval “opened a tremendous number of doors for us,” says Sepp, especially in gaining the attention of leading neurologists around the world who specialize in Huntington’s disease.
Among the neurodegenerative diseases potentially attacked by Oxalys drug candidates, Huntington’s made a logical first target for trials because it is a dominant genetic disorder, driven by mutations of a single gene.
“If one parent has it, then their children have a 50/50 chance of inheriting the disease gene, and if you have the disease gene then you have a 100% chance of developing the disorder,” Sepp says. “We know exactly who will develop the disease, and usually the severity of the disease is similar in these families.” That means that when researchers enlist patients for a clinical trial on Huntington’s, researchers can choose those who will give clearest results on a drug’s effectiveness.
In contrast, scientists can’t predict who will develop Alzheimer’s and how their disease will unfold. “That means you need huge patient populations over a long period of time, which is very cost-intensive,” she notes.
Oxalys is actively developing drug candidates for not only Huntington’s disease but Parkinson’s disease, and hopes to broaden its focus to Alzheimer’s disease as well over time.
The three diseases all are tied to aging, when cell mechanisms such as the ability to control protein quality start to decline, Sepp points out. “If you can find compounds to improve protein quality control, those compounds are likely to be broadly neuroprotective so they will be applicable to all of these major neurodegenerative disorders,” she says. “Treating all of these diseases is our ultimate goal.”