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ILP Institute Insider

November 23, 2015
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Defending the Brain

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.
Katharine Sepp
Co-founder & CEO
Oxalys Pharmaceuticals
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.

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.
Joost Schulte
Co-founder & CSO
Oxalys Pharmaceuticals
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.”

MIT Startup Exchange (STEX) is an initiative of MIT’s Industrial Liaison Program (ILP) that seeks to connect ILP member companies with MIT-connected startups. Visit the STEX website and log in to learn more about Oxalys and other startups on STEX.

Research News

November 16, 2015

“Shrinking bull’s-eye” algorithm speeds up complex modeling from days to hours

To work with computational models is to work in a world of unknowns: Models that simulate complex physical processes — from Earth’s changing climate to the performance of hypersonic combustion engines — are staggeringly complex, sometimes incorporating hundreds of parameters, each of which describes a piece of the larger process.

Parameters are often question marks within their models, their contributions to the whole largely unknown. To estimate the value of each unknown parameter requires plugging in hundreds, if not thousands, of values, and running the model each time to narrow in on an accurate value — a computation that can take days, and sometimes weeks.

Now MIT researchers have developed a new algorithm that vastly reduces the computation of virtually any computational model. The algorithm may be thought of as a shrinking bull’s-eye that, over several runs of a model, and in combination with some relevant data points, incrementally narrows in on its target: a probability distribution of values for each unknown parameter.

MIT Sloan
Management Review

November 16, 2015

Are You Part of the Email Problem?

“If we email each other three times over the same issue, it’s time for one of us to pick up the phone.”

That sentence is posted at author and consultant Phil Simon’s website, on his page “Working With Me.” Simon also adds, at his website, “If you will only communicate by email, then probably we shouldn’t work together. Don’t get me wrong. Email is fine. I send many messages every day. But it’s only one form of communication; it is not the only one.”

Over-reliance on email is one of Simon’s pet peeves — so much so that he devotes much of his new book, Message Not Received: Why Business Communication Is Broken and How to Fix It (Wiley, 2015), to it.

Email is a terrifically useful tool, but it suffers from significant limitations. “People already use email as a catch-all for personal communications, business communications, de facto project management, task management,” says Simon. It’s past time, he maintains, for businesses to shift many of those jobs out of email and into complementary tools such as Dropbox, Asana, Basecamp, HipChat, Jive, Yammer, and Slack. The result, he says, will be much better communication and far less wasted time.

Simon talked with Gerald C. (Jerry) Kane, an associate professor of information systems at the Carroll School of Management at Boston College and guest editor for MIT Sloan Management Review’s Social Business Big Idea Initiative, about how organizations can cut back on email and its evil business communication twin, jargon.