Rare genetic mutation carriers potentially left neglected amidst advancements in molecular medicine, yet fresh optimism arises.
Rewritten Article:
Emily Kramer-Golinkoff is battling for every breath. Advancing cystic fibrosis makes even basic tasks like walking or showering an uphill struggle. She's one of the 40,000 Americans living with the most common fatal genetic disease in the US, but her case is unique—it's caused by a rare genetic mutation that conventional treatments can't touch.
Life-saving advancements in genetic science are illuminating the hidden villains behind these brutal diseases and paving the way for treatments. However, patients with these ultra-rare mutations often face fewer options and slimmer odds—many are now looking to experimental gene therapies as a beacon of hope.
"It's hard to watch our friends pull themselves up from the brink, while we're left behind," shares Kramer-Golinkoff, a 40-year-old cystic fibrosis warrior. "We're eager and desperate to join them."
It's not just science that's standing in their way, it's economics. Pharmaceutical companies have a natural inclination to target the most common mutations, creating a form of discrimination for those less common cases.
"To spark a company's interest, you need a substantial patient pool in a major market,” explains Dr. Kiran Musunuru, a gene editing expert from the University of Pennsylvania. "Unfortunately, this means many rare cases get overlooked."
Charities, including the nonprofit Kramer-Golinkoff co-founded, Emily's Entourage, are working tirelessly to breach this barrier. Fundraising efforts have helped kick-start gene therapy that could help patients irrespective of mutation.
Despite the wait, "just having these therapies undergoing trials provides such hope," says Kramer-Golinkoff.
Kramer-Golinkoff was only six weeks old when she was diagnosed with cystic fibrosis, a condition that causes thick mucus to accumulate throughout the body. As the malfunctioning CFTR protein is not manufactured or misfunctions, chloride gets trapped in cells, leaving the cell surface dry. This results in mucus buildup that can cause damage, blockages, and infections in the lungs and other affected organs.
"As I've grown older … my CF has grown worse, despite my best efforts to postpone it," Kramer-Golinkoff shared.
Before her health took a turn for the worse, she managed to complete a master's degree in bioethics at the University of Pennsylvania, hold down a job, travel, and socialize. But she developed CF-related diabetes and other complications. Isolated during the pandemic, she's been living with her parents in Greater Philadelphia.
"Cystic fibrosis is a relentless beast," she admit.
In contrast, others with the condition have seen remarkable improvements in their health with "CFTR modulator" therapies. These treatments work for people with the most common mutation and fix the malfunctioning protein. Studies show these medications significantly improve lung function, respiratory symptoms, and overall quality of life.
However, these treatments don't work for people with rare mutations and for patients whose disease-causing mutations remain unknown or understudied. Mutations may be unknown because genetic testing isn't widespread in areas like developing nations or because they're uncommon or difficult to detect.
Testing companies, such as GeneDx, have made some headway in screening diverse populations, yet disparities persist.
For instance, cystic fibrosis data among African populations is scarce—affecting people on the continent, as well as those with ancestry linked to the continent. Research shows that Black cystic fibrosis patients are more likely than their white counterparts to be among the 10% who don't respond to CFTR modulator therapies.
While it's improbable we can change the market dynamics, researchers suggest a solution lies in developing "mutation-agnostic" gene therapies targeting all patients with a disease. This strategy has shown promise in treating diseases of the retina as well as cystic fibrosis.
"We're in the midst of a gene therapy revolution," says Dr. Garry Cutting of the Johns Hopkins Cystic Fibrosis Center.
Most of the 14 experimental gene therapies in development for the disease target patients regardless of mutation, aiming to provide a correct version of the CFTR gene to cells. This would allow cells to produce normal proteins, no matter what mutation is causing a patient to produce insufficient or non-functional CFTR proteins.
One treatment, partially funded by the Cystic Fibrosis Foundation, is being developed by Spirovant Sciences, a company Emily's Entourage provided seed funding to launch. The first patient participated in a 53-week clinical trial at Columbia University, which aims to determine if the therapy is safe and how long it stays active in the lungs.
At this stage, Kramer-Golinkoff's condition continues to deteriorate. She now has just 30% lung capacity, struggles with kidney problems, and has high blood pressure in her lungs. Managing her diabetes with insulin and a variety of medications, she finds herself faced with the tough decision of conserving energy on a daily basis.
"Everyone with CF has big dreams and vital work to do. It's challenging when you're forced to make conscientious choices about energy conservation. But we're excited about the promise of gene therapies. They can't come quickly enough."
- Emily Kramer-Golinkoff, a cystic fibrosis warrior, battles with every breath due to a rare genetic mutation that conventional treatments can't address.
- Unique cases like Kramer-Golinkoff often face fewer options and slimmer odds, making experimental gene therapies a beacon of hope.
- Kramer-Golinkoff shares her frustration, "It's hard to watch our friends pull themselves up from the brink, while we're left behind."
- Pharmaceutical companies typically target the most common mutations, leaving fewer options for those with rarer cases.
- Dr. Kiran Musunuru, a gene editing expert from the University of Pennsylvania, explains this market trend, stating, "To spark a company's interest, you need a substantial patient pool in a major market.”
- Charities, including Emily's Entourage—a nonprofit co-founded by Kramer-Golinkoff—are working tirelessly to breach this barrier and kick-start gene therapy for all patients, irrespective of mutation.
- Kramer-Golinkoff highlights the hope gene therapies bring, saying, "Just having these therapies undergoing trials provides such hope."
- Researchers suggest a solution lies in developing "mutation-agnostic" gene therapies, targeting all patients with a disease, including those with rare or undetected mutations, potentially revolutionizing the treatment landscape for chronic diseases like cystic fibrosis.
