The Last Mile

If you were making the case for the miracle of modern medicine, you’d find few better examples than Cystic Fibrosis (CF).

When CF was first discovered in 1938 – initially classified as a disease of mucus plugging the glandular ducts – the average life expectancy was six months. Since this blockage affected the Gastrointestinal (GI) system, the disease was described as malabsorption and failure to thrive.

“Many of those who were initially diagnosed with CF died of malabsorption. From the outset, it was thought of as a GI disease,” said Megan Gabel, M.D., pediatric Gastroenterology Specialist in the Division of Gastroenterology, Hepatology and Nutrition.

Since then, the medical world’s understanding of CF – and ability to treat it – has grown tremendously.

From its origins as primarily a GI disease, CF is now understood as a genetic disorder that affects the DNA and RNA of cells that produce mucus, sweat and digestive juices. This significantly increases the risk of severe infections to the lungs, digestive system and other organs in the body.

However, thanks to the breakthrough treatment of transmembrane conductance regulator (CFTR) modulator therapies – which were first approved in 2012, followed by approval of an almost universally effective modulator in October of 2019 – CF patients are now living well into middle age. This, in turn, has increased the importance of transitional medicine and day-to-day management to improve their quality of life. Even before these therapies, years of investment from the CF Foundation toward specialized clinical teams had already made significant advancements.

“We’re at the point where patients can focus on more than taking their next breath,” said Gabel. “From a GI standpoint, we’re finding more avenues where we can help. Patients now can monitor different issues that arise as they age, such as increased risk of colon cancer.”

The same improvements are being seen in the area of lung infections which, next to GI, is the most common part of the body where CF complications arise, according to Karen Voter, M.D., pediatric pulmonology specialist at GCH.

“We still look for all the same things – lung infections, airway clearance issues – but we find them less often,” she said. “In the past, we would have 2-3 people in the hospital at all times. Now, it’s practically nobody.”

The mRNA Potential

Despite these major advances, between 5-10 percent of CF patients can’t be treated by the modulators. There are more than 2,000 genetic mutations that can cause CF, and some of them are so rare that fewer than five people share them. As a result, it’s extremely difficult to conduct statistically significant research on these patients, much less develop modulator therapies that can target and alter the abnormal protein that causes CF.

For these patients with the most severe, rarest mutations, there is hope that mRNA-based treatments – now in the spotlight due to their success in fighting COVID – can help cure them.

Yi-Tao Yu, Ph.D., professor in the Department of Biochemistry and Physics, has been studying RNA for 30 years. The recent breakthroughs in mRNA technology for the COVID vaccines have come after a rollercoaster of failures and false starts.

“A lot of people gave up on RNA,” said Yu, “nothing really happened for years. But because of persistence you found improvements.”

In particular, the improvement of the delivery system of RNA into the cell helped advance research to the point where viable therapeutics could be developed.

“RNA is really prone to degradation if you don’t get it to the cell. It took years of research successes and failures to get RNA to the right place in the body. Now, you can modify the RNA and make it stable and more accessible to cells.”

With these recent advances, researchers have been focusing their efforts on using mRNA technology to treat a variety of diseases. Due to theories that have been formulated over time by URMC professor Lynne Maquat, Ph.D., CF is considered one the likeliest diseases to be treated by mRNA.

In 1980, Maquat traveled to Jerusalem to retrieve bone marrow samples from four children suffering from thalassemia major, the most severe form of the inherited blood disorder thalassemia. Maquat wanted to learn why the children’s marrow contained no beta-globin protein, which is necessary for the oxygen-carrying function of red blood cells. Her 1981 breakthrough manuscript, “Unstable beta-globin mRNA in mRNA-deficient beta0 thalassemia,” published in Cell, was the first to reveal the role of nonsense-mediated mRNA decay (NMD) in human cells.

NMD is a quality control mechanism that removes flawed messenger RNA molecules that, if left intact, would lead to the production of abnormal proteins that could be toxic to cells and initiate disease. This NMD also produces what is called a premature stop codon, which stops the translation of mRNA on a cellular level, which in turn generates a shortened or truncated protein that is non-functional.

This termination of mRNA, in which only a small fraction of the protein escapes, results in the most severe cases of CF – those that can’t be treated by the modulators. With new support from the CF foundation, Yu’s lab is in the process of researching mRNA therapies for these patients.

“We’re developing a technique to modify the RNA to reverse the nonsense codon back to the sense codon, so it can produce the full-length protein,” he said. “We have shown that in human cells we can make it work and reverse it, we can suppress nonsense mediated decay and detect the full-length protein using one site-specific modification.”

Yu’s lab will begin testing this process on animal models, with the hope of presenting the findings at a research conference in San Antonio in the Fall. For Yu, the recent shift of attention toward mRNA therapeutics is a welcome direction that bodes well for further progress.

“mRNA treatment for CF is getting a lot of attention lately, and it’s a good sign” Yu said. “We had the lab in place and the resources to scale-up, and the COVID vaccines gave us additional momentum.”

The Long-Term View

While Yu’s lab is at the forefront of helping develop mRNA therapies to treat the most severe CF patients, Gabel and Voter have received sustained support from the CF foundation to treat pediatric patients. Since 2015, Gabel has helped implement treatment standards recommended by the CF Foundation’s Digest Group program, which established optimal BMI and dietary guidance to prevent risks of reflux, intestinal blockage, and liver disease.

“We had better outcomes even before the modulators were approved,” Gabel said.

After the CTFR therapies were approved, both Voter and Gabel received grant support from the CF Foundation to study their long-term effects. The study began enrolling patients in December 2019, and will monitor patients’ respiratory status, liver characteristics, bone health, endocrine system, and diabetes risk every six months for several years. Thus far, side effects have not been debilitating, and the benefits of the modulators have outweighed them.

“Patients on these modulators have told me, ‘I don’t feel like I have CF,’” said Voter. “It’s gotten to the point people don’t want to do the routine therapies because they feel they don’t need it anymore. We’re studying the effects of those decisions.”

While the therapies are life-changing, CF patients still face many challenges as they grow older, and maintaining routine care is critical, according to Steven Scofield, M.D., professor of clinical pediatrics in the Division of Transitional Care Medicine.

“CF is now a lot like HIV; 20 years ago it was a fatal disease in which patients died from complications in their immune system. Now it’s more of a chronic, outpatient disease,” he said. “We’re helping patients with conditions they wouldn’t have lived long enough to develop before, like hypertension. In addition, CF patients are 30 to 40 percent more likely to develop diabetes.”

The prospect of CF patients living long enough to develop these later-life diseases is, in itself, a massive improvement that reflects years of increased awareness and support. When Scofield got involved with CF 20 years ago, he had to treat adults in a pediatric clinic because financial resources and infrastructure to care for patients was stretched thin. After partnering with Rochester General Health to run his clinic at Culver Medical Group, Scofield settled at URMC’s Complex Care Center (CCC) in 2016, which includes dedicated staff to address all forms of complex illnesses.

Gabel and Voter – along with other CF clinicians – work together extensively to help transition adults to Scofield’s care. “We have a meeting once a year to go over the patients that turn 18 or 19. We communicate with them and have meetings with the adult center with regards to research. When we have the yearly transition meeting, and when the patients are ready, adult providers will come to meet them. We also help connect them to social workers,” said Voter.

Over time, Scofield’s adult CF population has grown from 60 to 99 patients, and the adult program itself is now bigger than the pediatric one. Similar to what Voter and Gabel have experienced, Scofield had seen the quality of life of CF patients improve even before the advent of modulators, due to the long-term cultivation and training of doctors with specialized skillsets around CF.

“We serve as generalists that can help with a majority of issues that arise from CF, everything from depression and anxiety to pulmonology,” he said.

With modulators, care centers concentrate on helping patients understand and manage the side effects, as well as continue to manage their regular therapies.

“Since it can be such a debilitating disease that causes shortness of breath and excessive coughing, many patients say, ‘I’ll deal with this medicine because I haven’t been to the hospital in a year.’ Or, ‘I’ve had my best sleep in forever,’” said Scofield

Given these advances, and thanks to the collaborative effort of URMC clinicians and researchers, the outlook for CF patients in the region and beyond is better than it’s ever been.

“It’s become a disease in which we’re controlling it, managing it, and keeping patients out of the hospital,” said Scofield.