CIRM funded study may help explain why some people with cystic fibrosis are less prone to infection

Dr. Kelly A. Frazer, UC San Diego School of Medicine

Cystic fibrosis is a disorder that mostly affects the lungs. It is caused by a mutation in a gene called cystic fibrosis transmembrane conductance regulator (CFTR). As a result of this mutation, cells that produce mucus (a slimy substance like the one in your nose) secrete a thicker-than-normal mucus that can create blockages in the lungs and digestive system. In the lungs, this thicker mucus is a perfect breeding ground for bacteria, leading to more chronic lung infections in those with cystic fibrosis.

However, some people with cystic fibrosis don’t develop lung infections as early or as often as others with the disorder. Thanks to a CIRM funded study, Dr. Kelly Frazer and her team at the UC San Diego School of Medicine have discovered why this might happen.

In healthy people, the CFTR protein is embedded in the membrane of most cells, where it forms a channel for chlorine ions. In people with cystic fibrosis, an inherited mutation in the CFTR gene means their channels don’t work as well and cells produce more mucus. The RNF5 protein inhibits CFTR, so people with cystic fibrosis who have genetic variations that decrease RNF5 expression have CFTR channels that function a little better, and thus aren’t as prone to infections as people with high RNF5 expression.

Before we get into that, we need to dive a bit deeper into cystic fibrosis and what causes this thicker-than normal mucus. In healthy people, CFTR is embedded in the membrane of most cells, where it forms a channel that allows chloride – a component of salt – to travel through. This flow ensures that cells have the right balance of salt and water. In people with cystic fibrosis, the CFTR mutation means that the channel doesn’t work as well, the flow of water is blocked resulting in more thick and sticky mucus. There are medications that can help boost CFTR, but they are very expensive and don’t work for everyone.

Dr. Frazer and her team discovered that a gene, called RNF5, also prevents CFTR from functioning well. People with cystic fibrosis who have lower levels of RNF5 have channels that function better, with less mucus build up, compared to people with higher levels of RNF5. This could potentially explain why some with cystic fibrosis get more chronic lung infections compared to others with the condition.

In a press release by UC San Diego School of Medicine, Dr. Frazer talks about how RNF5 could play a role in treating patients.

“The cystic fibrosis field is trying to figure out what are the modifiers across the genome that increase or decrease the probability that an individual patient will respond to these expensive drugs. RNF5 may be one of these modifier genes.”

In the same press release, Dr. Matteo D’Antonio, a project scientist in Dr. Frazer’s lab, talks about how these findings could result in more personalized treatments for people with cystic fibrosis.

“This study uncovered a new aspect of cystic fibrosis — one that could lead to new drug design and development, and allow clinicians to better tailor treatments.”

The full study was published in eLife.

Rare Disease, Type 1 Diabetes, and Heart Function: Breakthroughs for Three CIRM-Funded Studies

This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.

Rare Disease

Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2. 

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.

However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.

Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains. 

In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,

“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”

Type 1 Diabetes

Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.

The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.

“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”

Heart Function

Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.

In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,

“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”

The full results of this study were published in Nature Genetics.