For almost every major common disease, researchers have less understanding of the severe forms than milder cases. And as a result, people with severe forms of diseases often have few treatment options available.
Thus, the significant unmet medical need for many diseases ranging from multiple sclerosis to Alzheimer’s is to halt disease progression and treat severe forms of the disease. “Most patients eventually do progress. We don’t understand what is causing that progression,” said Dr. Jeffrey Gulcher, chief scientific officer of Genuity Science (Boston).
What causes disease progression?
This basic concept concerning disease severity is evident in a range of clinical areas. Consider, for instance, non-alcoholic fatty liver disease, where abnormal amounts of fat are stored in the liver. Roughly one in four people in the U.S. have the condition, which can progress to non-alcoholic steatohepatitis (NASH) in a limited number of individuals. “Most of us can walk around fine with plenty of fat in our liver, and it doesn’t really affect us,” Gulcher said. “But a small percentage of people who do have fatty liver disease ultimately develop fibrosis or cirrhosis.”
A similar theme is evident in diseases ranging from asthma to multiple sclerosis (MS). “In MS, the unmet medical need is for the progressive forms of the disease, where after each attack, the patient doesn’t fully recover,” Gulcher said.
The most common form of multiple sclerosis, however, is relapsing-remitting MS, where patients deal with periodic attacks of symptoms that can include fatigue, dizziness and vision problems.
“What leads to long-term disability and progression to a wheelchair, typically, are the two major progressive forms of MS,” Gulcher said.
One form is primary-progressive MS, where neurologic function gradually worsens after the onset of symptoms. The other form is secondary-progressive MS, which starts with the relapsing-remitting form before progressing into a more progressive form of the disease with increasing disability.
“It turns out that almost all drugs today are labeled for the relapsing-remitting form of MS, which try to reduce the number of recurrences of MS attacks,” Gulcher said.
Similarly, available drugs for conditions such as Parkinson’s and Alzheimer’s treat symptoms rather than the underlying progressive nature of those conditions.
A structured approach based on genomics
One requirement to better treat severe forms of MS, Alzheimer’s, Parkinson’s and other diseases is detailed clinical data with a standardized approach to evaluating disease progression. For MS, this would include categorizing patients according to the three types of the disease and following them over time. “It’s important also to have disability scores that allow you to sort of follow the progression of patients as they either decline or remain stable,” Gulcher said.
“You need to have enough detailed clinical information to distinguish between severe sub-forms of disease and less severe sub-forms of disease,” Gulcher said, adding that few genetic studies have that depth of clinical data.
Genomic data can provide more clues. “We’ve already sequenced the genomes of about 9,000 multiple sclerosis patients, and we’ve tried to enrich that cohort with more progressive disease,” Gulcher said. The company has worked to optimize the power of patients with progressive disease forms and those without symptom progression.
In its MS research, Genuity has collaborated with Dr. Stephen Sawcer, a professor at the University of Cambridge. The resulting Genuity Science MS research study has genomic data on roughly 9,000 patients. “Ultimately, we expect to have about 12,000 multiple sclerosis patients sequenced, combining more samples from the U.K. and Ireland,” Gulcher said.
Of course, environmental factors often play a role in diseases such as MS, but focusing on the environmental factors involved in disease can be challenging — especially considering how several theories concerning disease etiology have been debunked or are unclear.
Conversely, focusing on the genetics component of conditions like MS can support a systematic approach of looking for differences between MS patients and controls. “You can look at the entire genomes across those two different MS controls in a much more systematic way than you can when looking for environmental factors,” Gulcher said. “Plus, it gives you the opportunity of looking for key pathways that might be driving progressive MS, so that you have an opportunity of making a drug versus if you have an environmental factor, you might not be able to intervene very easily with that.”