The genes behind an inherited heart condition, using AI to assess symptoms in ALS, and the rare disease regulatory arena. More live coverage from the Charles River World Congress   

The emergence of genomics has made it possible to understand the biological underpinnings of a rare disease much more quickly, and technologies like CRISPR gene editing promise to usher in new ways of correcting or compensating for disease-causing mutations. In the second and final day of the Charles River World Congress we heard about how researchers are using genomics to develop and deliver drugs for untreatable conditions at face. We also heard about an effort to customize a drug and deliver it to the patient in an unusually tight timeframe, and the use of Google algorithms to help patients with ALS communicate. Here is a shap shot of some of yesterday’s talks.

Finding the diseases associated with variants

South San Francisco startup Maze Therapeutics, launched two years ago by venture capitalist Third Rock Ventures, was created to make sense of the plethora of human genetic data. Central to its mission is why some people with particular mutations linked to a certain disease get sick, while others carrying the same mutation do not.  

Dr. Eric Green, PhD, who helped to launch Maze Therapeutics and is now its VP of R&D, says the reason for the disease patterns is not just dumb luck. It could be that the genetic variant causing the disease is modified by other genes in our DNA.

Dr. Green kicked off Day Two of the World Congress with a look at how sequencing technology and techniques for genetic analysis are helping us to identify new targets for cancer, high cholesterol, and rare diseases like the inherited cardiovascular disease hypertrophic cardiomyopathy (HCM) caused by a mutation that leads the heart to contract excessively.

HCM is the most common cause of sudden cardiac death among athletes, though it is mostly a consequence of older individuals with atrial fibrillation. HCM was first described in 1949, and the gene causing the condition was identified in 1990. While there are open-heart surgeries that can decrease symptoms, there are no FDA-approved treatments for HCM; patients who have the disorder are typically prescribed drugs that treat hypertension, heart failure, or beta blockers.

MyoKardia, another startup launched by Third Rock, is hoping to improve treatment options for a rare subset of HCM patients with obstructive HCM, a thickening of the heart walls that blocks blood flow and in some cases, leads to sudden cardiac death. Green, who was also part of MyoKardia, is developing a small-molecule drug, now in Phase III trials, that is designed to reduce the contractions that cause the heart’s walls to thicken. The targeted drug corrects the underlying defect that causes HCM and, in doing so, demonstrates the ability to modulate cardiac muscle contraction.

Green, who worked on the drug while he was at MyoKardia, said tests in mice were a big turning point in their research because they were able to observe the downstream effects of the therapy.

MyoKardia is now funding Sarcomeric Human Cardiomyopathy Registry (SHaRe), a first-of-its-kind effort that is advancing the understanding of HCM and dilated cardiomyopathy, another heritable heart disease.  The project supports research, clinical development and patients, said Green. Importantly, it is a built-in repository of scientific and clinical data that could lead to more therapies.

“Fundamental changes of human genetics are changing the entire paradigm in how we identify the target to how we get it approved,” says Green.

Voice Recognition Tools in the Assessment of ALS

One of the hallmark features of people with amyotrophic lateral sclerosis (ALS) is loss of voice control. As the disease progresses it becomes harder and harder for patients with ALS to communicate. The ALS Therapy Development Institute (ALS TDI) is using machine learning to develop tools that allow the words of ALS patients to be transcribed.

Fernando Vieira, Chief Scientific Officer of ALS TDI, said Google software is being used to turn recorded voice samples into a visual representation of the sound. The computer then uses common transcribed spectrograms to train the system to better recognize the less common type of speech. The ALS Residence Initiative is also a partner in this venture.

To build the tools that facilitate verbal communication, ALS TDI, began recruiting people with ALS willing to record their voice. (A recurring phrase is “I owe you a yo-yo today.)  

“I have listened to probably 90% of these recordings,” says Vieira. “When you get down to a functional rating score of zero, it can take them 45 seconds to get that yo-yo out. They are working very hard to contribute their voice. It is extremely meaningful to us that they are contributing the data.”

Some ALS patients have recorded hundreds and even thousands of specific phrases in order to train and optimize Google’s AI-based algorithms. As a result, mobile phones and computers can more reliably recognize and transcribe the phrases expressed. The goal is to allow people with ALS to independently send text messages or to generate spoken commands using Google Home devices.

At the end of his talk, Charles River announced that it was awarding US$8,000 to ALD TDI to support its work in advancing research to cure ALS and prolonging the independence of people with neurodegenerative disease.

Rare Disease Drugs: Picking up the Regulatory Pace

Getting a drug to market takes upwards of 10 years, but there are quicker avenues forward for rare disease drug makers. Martine Zimmermann of Alexion Pharmaceuticals noted the jump in orphan drug approvals that was seen after the FDA implemented the Breakthrough Therapy Designation – an expedited process for drugs that are meant to treat serious illnesses that are not sufficiently covered by other therapies.

She mentioned that several countries, including the EU and Japan, have created new workflows to push through drugs that fill unmet medical needs. In order to successfully navigate these regulatory hurdles, she recommends close communication and collaboration between players in academia, patient families, companies, and regulators.

She urged drug developers not to be afraid to keep in contact with regulators at every stage in order to ensure that every box is checked on the way to bringing a novel drug to market. 

Wearing ALL the Hats: From Impossible to Possible 

The final word of the 3rd World Congress came from Dr. Allyson Berent, a veterinarian, Chief Operating Officer of GeneTx Biotherapeutics, and mother of Quincy who has Angelman syndrome. Dr. Berent mentioned that she has always had a hard time with telling pet owners when nothing could be done, and she said she started not taking no for an answer early in her career when it came to helping her patients. That attitude continued when she was given her daughter’s devastating diagnosis. 

 Listen to this episode of Eureka’s Sounds of Science to hear more about Dr. Berent’s incredible story.