Scientists at Houston Methodist have created a treatment with the potential to address cardiovascular aging caused by a disease that promotes early heart failure in children. The groundbreaking discovery would benefit those facing age-related heart complications. For children battling Hutchinson-Gilford progeria syndrome, it could mean an extension of life.

Progeria is estimated to occur in 1 in 20 million people, which is just under 400 children around the world. It’s a population of patients who are running out of time and in need of real progress. Currently there’s no cure for progeria, but John P. Cooke, MD, PhD, Joseph C. “Rusty” Walter and Carole Walter Looke Presidential Distinguished Chair in Cardiovascular Disease Research, and researchers at Houston Methodist are looking to change that.

Cooke and his team at Houston Methodist have shown that the ends of chromosomes, known as telomeres, are shortened in patients with progeria.

As we age, our telomeres erode over time, leading to shortened telomeres in older adults. However, the telomeres in affected cells of patients with progeria are often shorter than cells from unaffected relatives. The shortened telomeres ultimately elicit a DNA damage response that results in accelerated aging and reduced cell lifespan. This leads to patients having heart attacks or strokes by the time they are teenagers.

At the Houston Methodist Center for Cardiovascular Regeneration, Cooke and his team have developed a method to extend the telomeres in children with progeria and arrest cellular senescence, which could be the key to reversing the detrimental effects of the disease.

“When you see these kids, they’re like every other kid. They want to play, they want to dream. They want to grow up and do something great,” said Cooke. “But they can’t do that. They don’t have the chance. That, alone, is reason enough for me to pursue this approach.”

Transient expression of telomerase mRNA extends telomeres in progeria-mutated cells

The team at Houston Methodist has been diligently researching the disease since 2014, with the objective of determining what impact extending telomeres could have on cells. Cooke’s team utilized an RNA delivery system that gave the progeria cells purified human telomerase reverse transcriptase (hTERT) mRNA to increase telomerase activity.

The hTERT mRNA treatment extended the telomeres in the progeria cells and restored the cellular function, thereby increasing the cellular lifespan. The untreated cells, on the other hand, continued to age. 

“We saw that when we reverse telomere shortening in progeria cells and [instead increase their length,] it reverses many of the problems associated with aging,” said Cooke.

“The telomere-extending technology [has] a significant effect on the ability of cells to multiply. They [can] function and divide more normally, and we [give] them extra lifespan as well as better function,” said Cooke. “Even markers of cellular aging [are] reversed.”

Upon examination, the researchers also found that hTERT mRNA improved nuclear morphology, or nuclear shape, which was likely due to the telomere extension. A typical nucleus of progeria cells appears with multiple folds, but when treated with the RNA delivery system, the nucleus takes on a more normal shape.

hTERT mRNA treatment restored the nuclear morphology of a progeria-mutated cell.

In order to arrive at this point, Cooke and his team needed to develop the RNA therapeutic resources at Houston Methodist’s RNAcore facility. The team’s development of the RNAcore led to faster discovery of the treatment approach.

RNAcore: The foundation for Cooke’s research and RNA therapies

Long before the study began, Cooke realized there was a national need for reliable, high quality RNA therapeutic materials that met FDA standards. Therefore, he helped establish the RNAcore Initiative as a supportive entity for the Progenitor Cell Biology Consortium with funding from the National Heart, Lung, and Blood Institute.

Today, Houston Methodist’s RNAcore has grown tremendously. The Cancer Prevention & Research Institute of Texas recently awarded RNAcore with $4.8 million to generate RNA constructs for research communities in Texas and around the world. Researchers can now access custom research-grade and clinical-grade RNA therapeutics and delivery strategies for use in fundamental clinical applications, including cardiovascular regeneration and cancer therapeutics.

“The RNAcore [was] the first entity in Texas to generate the new class of drugs to modify the function of cells in a beneficial manner,” said Cooke.

Prior to joining Houston Methodist, Cooke was at Stanford University, where he was the inventor of 30 patents, many of which are licensed by biotechnology companies. His passion for advancing cardiovascular care drove him to Houston Methodist, which has an infrastructure that fosters medical innovation and helps his team turn ideas into life-altering cures for patients quickly.

Accelerating progeria research

At Houston Methodist, we fuel and accelerate all stages of cardiovascular advances with technological expertise and onsite capabilities for FDA-compliant current good manufacturing practice (cGMP) and good laboratory practice (GLP) studies that streamline the process of delivering medicines from testing to handing off to the market for delivery to patients. Our facilities are built to provide a physical connection from the research institute to the hospital, giving researchers and physicians autonomy to advance their findings into clinical trials.

Cooke and his team represent the success of this model. Having the RNAcore on the same working grounds as the clinical team has bolstered their efforts to discover a potential avenue for treating progeria.

Preclinical studies with RNA therapy are underway with clinical trials to start soon, joining the 100+ cardiovascular clinical studies that are ongoing at the center.

 “What we’re focused on is improving people’s health,” Cooke told Houstonia in July. “We’re moving toward a therapy that will be transformational for these children. I do believe that.”

Cooke hopes that the findings from the progeria research will also help in making strides for the millions of patients who suffer from stroke or heart attack.

“Insights gained from rare disease research, like progeria, not only will help children with progeria live longer, but also will provide a greater understanding of [other] common aging-associated diseases,” said Cooke.