From EurekaAlert
Novel gene therapy approach creates new route to tackle rare, inherited diseases
Nonsense mutations are single-letter errors in the genetic code that prematurely halt the production of critical proteins. These unfinished proteins are unable to function normally, and nonsense mutations cause 10-15 percent of all inherited genetic diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, cystic fibrosis and polycystic kidney disease. There is currently no cure or broadly effective treatment for these often devastating conditions that are individually rare but estimated to collectively affect up to 30 million people worldwide.
A new study, led by Christopher Ahern, PhD, at the University of Iowa Carver College of Medicine, reveals a novel approach and robust technology platform for suppressing nonsense mutations using engineered transfer RNA (tRNA) molecules. The research by Ahern, his UI colleagues, and collaborators at The Wistar Institute in Philadelphia, the Cystic Fibrosis Foundation Therapeutics Lab in Lexington, Mass., and Integrated DNA Technologies Inc. in Coralville, Iowa, shows that modified tRNAs can efficiently and accurately repair nonsense mutations with any amino acid. The findings were published Feb. 18 in Nature Communications.
"Because nonsense mutations cause a wide range of severe, life threatening diseases, there is a significant unmet medical need to efficiently repair these stop codons in people having these inherited genetic alterations," says Ahern, UI professor of molecular physiology and biophysics and a member of the Iowa Neuroscience Institute. "Our unique gene therapy approach takes advantage of the built-in fidelity of the translation process but reengineers tRNAs to turn disease-causing stop signals back into the correct amino acid. Basically, our anticodon engineered tRNA technology turns 'stops' into 'gos' and hopefully one day may be used to correct defective genetic sequences in people."
The process of turning genetic code into protein is called translation. Transfer RNAs (tRNAs) match up with the blueprint code of the messenger RNA and deliver the correct amino acid in the correct order to build the protein. The code sequences of the messenger RNA, which dictate the order of amino acids, are called codons. The matching sequence on the tRNAs are called anticodons.
At the end of every protein coding sequence there is a genetic stop signal--a stop codon--that tells the protein production machinery to halt. Nonsense mutations occur when a mistake in the genetic sequence turns an amino acid codon in the middle of the protein into a stop codon.
Ahern and his UI team, including lead study author John Lueck, PhD, who is now at the University of Rochester, systematically tested the engineered tRNA molecules for their ability to repair premature stop codons with each of the 20 natural amino acids. The high-throughput screen efficiently identified multiple potent engineered tRNAs for each amino acid and stop codon type.
To demonstrate that the approach could work in more complex and physiologically relevant systems, Ahern lab members, together with collaborators at the Cystic Fibrosis Foundation Therapeutics (CFFT) lab and the laboratory of David Weiner, PhD, at The Wistar Institute showed that the engineered tRNAs when encoded and formulated for efficient delivery are expressed at high levels and are effective at correcting nonsense mutations in living mouse muscle tissue. Interestingly, the tRNA activity persisted for weeks in the delivered forms, suggesting this sustainable gene therapy approach may have potential for being used in the clinic one day.
Importantly, the team at the CFFT lab under William Skach, MD, showed that the tRNAs were selective in their activity and did not affect normal stop codons that signal the true end of the protein sequence.
And at the UI, Ahern with postdoctoral fellows Lueck and Danny Infield, PhD, and UI professor of pediatrics and cystic fibrosis expert Paul McCray, MD, showed that the approach could correct a CF-causing nonsense mutation and accurately produce a functional CFTR protein.
"What I like about this study is that a number of different labs with different expertise all verified our engineered tRNA technology in a variety of contexts," Ahern says. "That suggests the approach is robust."
Although he is excited about the potential for anticodon engineered tRNAs to tackle diseases caused by nonsense mutations, Ahern notes there are many scientific questions to answer and technical hurdles to overcome to find out if this approach can be translated into human therapies.
"For many diseases caused by nonsense mutations, even correcting a small percent of the mutated protein could be enough to be therapeutic to the patient," Ahern says. "If this were to work as a human therapy, we would have a way to target every known stop codon disease."
Living with PKD
Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary diseases, and is associated with complications such as intracranial aneurysm. A lack of screening guidelines prompted a group of researchers to evaluate the cost-effectiveness of various MR angiography strategies.
The results of the analysis were published online Feb. 19 in Radiology.
“There is uncertainty regarding the benefits of screening for intracranial aneurysm in patients with ADPKD owing to the lack of data from randomized, prospective clinical trials,” wrote Ajay Malhotra, of Yale School of Medicine in New Haven, Connecticut, and colleagues. “The initial age at screening, the frequency and duration of repeat screening, the use of surveillance imaging after intracranial aneurysm detection, and the utility of treatment of unruptured intracranial aneurysms in patients with ADPKD are not clearly defined.”
The authors created a Markov decision-analytic model to evaluate the costs and outcomes of five different MR angiography management strategies covering the lifespan of a patient up to 80 years old.
Overall, the best strategy is MR angiography screening every five years and annual follow-up in those with detected intracranial aneurysm. The strategy became more favorable when life expectancy is more than six years.
They also found if the rupture risk of unruptured intracranial aneurysm is between 0.015 percent and 0.35 percent, one-time MR angiography screening plus annual MR angiography follow up “may be dominant,” the authors wrote.
“Screening for intracranial aneurysms in patients with autosomal dominant polycystic kidney disease is cost-effective, and repeat screening every 5 years after a negative initial study should be considered,” the authors wrote. “Annual surveillance imaging may be optimal in patients with incidentally detected intracranial aneurysms and in the treatment of patients with growing, high-risk aneurysms.”
An Israeli digital health start-up called Healthy.io has developed an FDA-cleared at-home smartphone urinalysis test to help people test their kidneys for proteins, a sign of damage to the organ.
Thirty million Americans have chronic kidney disease, often due to diabetes and hypertension; that's 1 in 9 adults, according to the National Kidney Foundation.
Early detection makes an enormous difference in avoiding complications from kidney disease.
Chronic kidney disease is the modern-day plague in the United States, driven in large part by the nation's obesity epidemic. According to the National Kidney Foundation, 30 million Americans have chronic kidney disease, often due to diabetes and hypertension; that's 1 in 9 adults. More than 510,000 kidney patients are now on dialysis, and over 100,000 are on the kidney transplant list.
The cost of caring for these individuals is staggering. "Medicare alone spends $114 billion annually caring for Americans with all stages of chronic kidney disease," said Kerry Willis, chief medical officer at the National Kidney Foundation. "That doesn't include the costs to the private insurance industry."
Recognizing the trend, an Israeli digital health start-up called Healthy.io has developed an FDA-cleared at-home smartphone urinalysis test to help people test their kidneys for proteins, a sign of damage to the organ. Early detection makes an enormous difference in avoiding complications from kidney disease.
Healthy.io's urinalysis test, Dip.io, uses disposable strips and cups in conjunction with a smartphone camera to read and interpret results. Patients dip a stick in a self-collected urine sample, wait for it to develop, and take a picture of it against a card using the company's app. The image is anonymized and put on the cloud for more detailed diagnostic tests.
The test has been assessed with Geisinger Health in conjunction with the National Kidney Foundation, achieving a 71 percent adherence rate among patients with hypertension who never have been tested before.
Founder and CEO Yonatan Adiri said that since Dip.io received FDA clearance last year, he has been busy marketing the technology to hospitals and health systems. The company is targeting a few major patient categories, including pregnant women, diabetics and hypertensives most at risk for kidney disease, and women who believe they may have the symptoms of UTI (urinary tract infection).
A testing lab in the palm of your hand
Adiri, the former chief technology officer to Israeli President Shimon Peres, developed a passion for health technology early in his career. He realized the smartphone as a medical tool was a niche that would grow when his father used it to transfer CT scans after his mother had an accident while traveling in China a few years ago. That helped her get diagnosed and saved her life.
"My goal is to help turn the mobile phone into the lab of today," he said. "Advances in AI and computer vision technology are making this possible."
In early February, Healthy.io raised $18 million in a Series B financing round led by Aleph, an Israeli-based venture capital fund, to support growth across its existing markets and to fund the commercial launch of the product in the United States. It also has raised funds from Samsung NEXT and private investors. That brings its total funding to $30 million.
Healthy.io's products are currently available in Israel and the U.K., where it recently inked a deal with Walgreens Boots Alliance subsidiary Boots UK to introduce consumer-focused UTI testing at the company's locations. Its efforts have been supported by a partnership with Siemens Healthineers to use the company's urinalysis reagents.
The start-up is boosted by rapidly advancing smartphone technology. Digital urinalysis is the latest example of a trend toward home diagnostics driving a surging medical technology market. The first at-home pregnancy test appeared in the late 1970s, paving the way for a home-based medical test market. More recently, the internet, IoT, smartphones and advances in areas like genetic testing have driven sharp growth in a home-testing market that will soon surpass $300 million.
Much of the marketing driving sales of at-home tests, which include cloud-based monitors that beam medical results to doctors, tout ease of use and lowered barriers to clinical-grade health maintenance. But getting people to take tests, whether in a doctor's office or at home, is tricky. In the case of kidney disease, which the Healthy.io kit can screen for, only about 6 percent of people with hypertension and 39 percent of diabetes patients undergo proper testing.
It's still too early to know if Healthy.io's technology will be a game-changer in kidney testing, but if it does, it could have a big impact on curbing health-care costs — and saving lives. "The FDA is now approving clinical algorithms and outcomes derived by using a cellphone for urine testing. That's a big step in helping to democratize health care," said Michael Eisenberg, a partner at Aleph.
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