As gene therapies and small molecule drugs are being studied in clinical trials, companies increasingly see the value in hiring patients to help explain the potential benefits.
Biomedical corporations and government research agencies are now incorporating patient advocacy more than ever, says Alice Lara, president and CEO of the Sudden Arrhythmia Death Syndromes Foundation in Salt Lake City, Utah. These organizations have seen the effectiveness of including patient voices to communicate and exemplify the benefits that key academic research institutions have shown in their medical studies.
“From our side of the aisle,” Lara says, “what we know as patient advocacy organizations is that educated patients do a lot better. They have a better course in their therapy and their condition, and understanding the genetics is important because all of our conditions are genetic.”
Founded in 2016, Tenaya is advancing gene therapies and small molecule drugs in clinical trials for both prevalent and rare forms of heart disease, says Ali, the CEO.
The firm's first small molecule, now in a Phase 1 clinical trial, is intended to treat heart failure with preserved ejection fraction, where the amount of blood pumped by the heart is reduced due to the heart chambers becoming weak or stiff. The condition accounts for half or more of all heart failure in the U.S., according to Ali, and is growing quickly because it's closely associated with diabetes. It’s also linked with metabolic syndrome, or a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels.
“We have a novel molecule that is first in class and, to our knowledge, best in class to tackle that, so we’re very excited about the clinical trial,” Ali says.
The first phase of the trial is being performed with healthy participants, rather than people with the disease, to establish safety and tolerability. The researchers can also look for the drug in blood samples, which could tell them whether it's reaching its target. Ali estimates that, if the company can establish safety and that it engages the right parts of the body, it will likely begin dosing patients with the disease in 2024.
Tenaya’s therapy delivers a healthy copy of the gene so that it makes a copy of the protein missing from the patients' hearts because of their mutation. The study will start with adult patients, then pivot potentially to children and even newborns, Ali says, “where there is an even greater unmet need because the disease progresses so fast that they have no options.”
Although this work still has a long way to go, Ali is excited about the potential because the gene therapy achieved positive results in the preclinical mouse trial. This animal trial demonstrated that the treatment reduced enlarged hearts, reversed electrophysiological abnormalities, and improved the functioning of the heart by increasing the ejection fraction after the single-dose of gene therapy. That measurement remained stable to the end of the animals’ lives, roughly 18 months, Ali says.
He’s also energized by the fact that heart disease has “taken a page out of the oncology playbook” by leveraging genetic research to develop more precise and targeted drugs and gene therapies.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” says Melind Desai of the Cleveland Clinic.
Tenaya’s second program focuses on developing a gene therapy to mitigate the leading cause of hypertrophic cardiomyopathy through a specific gene called MYPBC3. The disease affects approximately 600,000 patients in the U.S. This particular genetic form, Ali explains, affects about 115,000 in the U.S. alone, so it is considered a rare disease.
“There are infants who are dying within the first weeks to months of life as a result of this mutation,” he says. “There are also adults who start having symptoms in their 20s, 30s and 40s with early morbidity and mortality.” Tenaya plans to apply before the end of this year to get the FDA’s approval to administer an investigational drug for this disease humans. If approved, the company will begin to dose patients in 2023.
“We now understand the genetics of the heart much better,” he says. “We now understand the leading genetic causes of hypertrophic myopathy, dilated cardiomyopathy and others, so that gives us the ability to take these large populations and stratify them rationally into subpopulations.”
Melind Desai, MD, who directs Cleveland Clinic’s Hypertrophic Cardiomyopathy Center, says that the goal of Tenaya’s second clinical study is to help improve the basic cardiac structure in patients with hypertrophic cardiomyopathy related to the MYPBC3 mutation.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” he says. “So this is an exciting new frontier of therapeutic investigation for MYPBC3 gene-positive patients with a chance for a cure.
Neither of Tenaya’s two therapies address the gene mutation that has affected Borsari and her family. But Ali sees opportunity down the road to develop a gene therapy for her particular gene mutation, since it is the second leading cause of cardiomyopathy. Treating the MYH7 gene is especially challenging because it requires gene editing or silencing, instead of just replacing the gene.
Wendy Borsari was diagnosed at age 24 with a commonly inherited heart disease. She joined Tenaya as a patient advocate in 2021.
Wendy Borsari
“If you add a healthy gene it will produce healthy copies,” Ali explains, “but it won’t stop the bad effects of the mutant protein the gene produces. You can only do that by silencing the gene or editing it out, which is a different, more complicated approach.”
Euan Ashley, professor of medicine and genetics at Stanford University and founding director of its Center for Inherited Cardiovascular Disease, is confident that we will see genetic therapies for heart disease within the next decade.
“We are at this really exciting moment in time where we have diseases that have been under-recognized and undervalued now being attacked by multiple companies with really modern tools,” says Ashley, author of The Genome Odyssey. “Gene therapies are unusual in the sense that they can reverse the cause of the disease, so we have the enticing possibility of actually reversing or maybe even curing these diseases.”
Although no one is doing extensive research into a gene therapy for her particular mutation yet, Borsari remains hopeful, knowing that companies such as Tenaya are moving in that direction.
“I know that’s now on the horizon,” she says. “It’s not just some pipe dream, but will happen hopefully in my lifetime or my kids’ lifetime to help them.”
AI was integral to creating Moderna's mRNA vaccine against COVID.
But the truth is that before ChatGPT nabbed the public’s attention, AI was already here, and it was doing more important things than writing essays for lazy college students. Case in point: It was key to saving the lives of tens of millions of people.
AI-designed mRNA vaccines
As Dave Johnson, chief data and AI officer at Moderna, told MIT Technology Review‘s In Machines We Trust podcast in 2022, AI was integral to creating the company’s highly effective mRNA vaccine against COVID. Moderna and Pfizer/BioNTech’s mRNA vaccines collectively saved between 15 and 20 million lives, according to one estimate from 2022.
Johnson described how AI was hard at work at Moderna, well before COVID arose to infect billions. The pharmaceutical company focuses on finding mRNA therapies to fight off infectious disease, treat cancer, or thwart genetic illness, among other medical applications. Messenger RNA molecules are essentially molecular instructions for cells that tell them how to create specific proteins, which do everything from fighting infection, to catalyzing reactions, to relaying cellular messages.
Johnson and his team put AI and automated robots to work making lots of different mRNAs for scientists to experiment with. Moderna quickly went from making about 30 per month to more than one thousand. They then created AI algorithms to optimize mRNA to maximize protein production in the body — more bang for the biological buck.
For Johnson and his team’s next trick, they used AI to automate science, itself. Once Moderna’s scientists have an mRNA to experiment with, they do pre-clinical tests in the lab. They then pore over reams of data to see which mRNAs could progress to the next stage: animal trials. This process is long, repetitive, and soul-sucking — ill-suited to a creative scientist but great for a mindless AI algorithm. With scientists’ input, models were made to automate this tedious process.
“We don’t think about AI in the context of replacing humans,” says Dave Johnson, chief data and AI officer at Moderna. “We always think about it in terms of this human-machine collaboration, because they’re good at different things. Humans are really good at creativity and flexibility and insight, whereas machines are really good at precision and giving the exact same result every single time and doing it at scale and speed.”
All these AI systems were in put in place over the past decade. Then COVID showed up. So when the genome sequence of the coronavirus was made public in January 2020, Moderna was off to the races pumping out and testing mRNAs that would tell cells how to manufacture the coronavirus’s spike protein so that the body’s immune system would recognize and destroy it. Within 42 days, the company had an mRNA vaccine ready to be tested in humans. It eventually went into hundreds of millions of arms.
Biotech harnesses the power of AI
Moderna is now turning its attention to other ailments that could be solved with mRNA, and the company is continuing to lean on AI. Scientists are still coming to Johnson with automation requests, which he happily obliges.
“We don’t think about AI in the context of replacing humans,” he told the Me, Myself, and AI podcast. “We always think about it in terms of this human-machine collaboration, because they’re good at different things. Humans are really good at creativity and flexibility and insight, whereas machines are really good at precision and giving the exact same result every single time and doing it at scale and speed.”
Moderna, which was founded as a “digital biotech,” is undoubtedly the poster child of AI use in mRNA vaccines. Moderna recently signed a deal with IBM to use the company’s quantum computers as well as its proprietary generative AI, MoLFormer.
Moderna’s success is encouraging other companies to follow its example. In January, BioNTech, which partnered with Pfizer to make the other highly effective mRNA vaccine against COVID, acquired the company InstaDeep for $440 million to implement its machine learning AI across its mRNA medicine platform. And in May, Chinese technology giant Baidu announced an AI tool that designs super-optimized mRNA sequences in minutes. A nearly countless number of mRNA molecules can code for the same protein, but some are more stable and result in the production of more proteins. Baidu’s AI, called “LinearDesign,” finds these mRNAs. The company licensed the tool to French pharmaceutical company Sanofi.
Writing in the journal Accounts of Chemical Research in late 2021, Sebastian M. Castillo-Hair and Georg Seelig, computer engineers who focus on synthetic biology at the University of Washington, forecast that AI machine learning models will further accelerate the biotechnology research process, putting mRNA medicine into overdrive to the benefit of all.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
