Hypoplastic Left Heart Syndrome

Researchers say an injectable hydrogel could mitigate damage to the right ventricle of the heart with chronic pressure overload. The research came out of the University of California San Diego, Georgia Institute of Technology and Emory University. Investigators published their work in Journals of the American College of Cardiology: Basic to Translational Science. For this study, they used rodents, but a 2019 FDA-approved Phase 1 trial demonstrated the hydrogel’s safety in humans who suffered a heart attack. As a result of the new preclinical study, the FDA approved an investigational new drug application (NDA). The teams at Emory and Georgia Tech can start a clinical trial with the hydrogel in pediatric patients in the coming months. In a post on the UCSD website, the researchers say they intended the hydrogel for children born with a condition that leaves them with an underdeveloped, nonfunctional left ventricle. This disorder, called hypoplastic left heart syndrome, comprises less than 4% of congenital heart defects. However, the researchers say it holds responsibility for 40% of deaths associated with heart defects in newborns. They cite a 35% survival rate in patients with this disorder. Currently, three open-heart surgeries before the patient turns five constitute the treatment options for this disorder. These surgeries reroute oxygenated blood to the right ventricle. Pediatric patients who survive into childhood post-surgery also receive medication and physical therapy while adhering to a special diet. According to the researchers, eventually, these patients experience right ventricle failure and require a heart transplant. “To the best of our knowledge, it’s the first time that an injectable biomaterial therapy has been evaluated to mitigate right ventricular heart failure,” said Jervaughn D. Hunter, the paper’s first author, out of UCSD. In the rodent study, injecting the hydrogel into the right ventricle improved function and allowed the heart to tolerate increased blood pressure and volume. The treatment also slowed down the rate of tissue scarring and maladaptive muscle growth. Researchers hope the hydrogel injection increases the amount of time the patient’s heart functions. This could lead to dramatically improved quality of life, better cognitive function and enhanced growth. Michael E. Davis, a senior author and professor of biomedical engineering at Georgia Tech and Emory, said this could enable the patients to wait until they can get on an adult heart transplant list. “This isn’t a cure, but our goal is to prolong a patient’s life,” said Karen Christman, a bioengineering professor at UCSD and the paper’s corresponding author. The hydrogel is made from cardiac extracellular matrix that is stripped of the cellular content through a cleansing process, dried and milled into powder form, then liquefied into a fluid that can be easily injected into the heart. Once it hits body temperature and pH, the liquid turns into a semi-solid, porous gel. It then encourages the patient’s own cells to repopulate areas of damaged cardiac tissue and to improve heart function. Researchers say that, in the preclinical trials, they first saw the effects of the treatment two weeks after injection. They also prepared the hydrogel with tissue from both the right and left ventricles of the pig hearts. With this, they found that tissues on each side of the heart differ “vastly.” Hydrogels from either side of the heart led to improved systolic function and reduced heart muscle growth and scarring while prompting arteriole formation and growth. Overall, though, they found that hydrogel derived from left-ventricle tissue proved more effective. The injected hydrogel also affected gene expression, specifically with pathways related to cardiac repair, including the development of the circulatory system, muscle structure and vasculature, plus the regulation of immune response and cellular response to oxygen-containing compounds. The team now hopes to begin recruiting for a clinical trial investigating the treatment’s efficacy in newborns with hypoplastic left heart syndrome.

An injectable hydrogel can mitigate damage to the right ventricle of the heart with chronic pressure overload, according to a new study. In 2019, this same hydrogel was shown to be safe in humans through an FDA-approved Phase 1 trial in people who suffered a heart attack. As a result of the new preclinical study, the FDA approved an investigational new drug application to start a clinical trial with the hydrogel in pediatric patients in the coming months, once institutional approvals are received. An injectable hydrogel can mitigate damage to the right ventricle of the heart with chronic pressure overload, according to a new study published March 6 in Journal of the American College of Cardiology: Basic to Translational Science. The study, by a research team from the University of California San Diego, Georgia Institute of Technology and Emory University, was conducted in rodents. In 2019, this same hydrogel was shown to be safe in humans through an FDA-approved Phase 1 trial in people who suffered a heart attack. As a result of the new preclinical study, the FDA approved an investigational new drug application for the Emory and Georgia Tech researchers to start a clinical trial with the hydrogel in pediatric patients in the coming months, once institutional approvals are received. In this case, the injectable hydrogel is intended for children born with a condition that leaves them with an underdeveloped, nonfunctional left ventricle. The disorder, known as hypoplastic left heart syndrome, comprises less than 4 percent of congenital heart defects. But it is responsible for 40 percent of deaths associated with heart defects in newborns. Patients with the disorder have a 35 percent survival rate. Current treatments consist of a series of three open heart surgeries all before the patient's 5th year of life that reroutes oxygenated blood supply to the right ventricle. Pediatric patients who survive into childhood after surgery also receive medication and physical therapy, as well as a special diet. But this palliative surgery comes at a cost. In a healthy heart, the right ventricle's job is to pump blood to the lungs; a job that entails dealing with blood at lower pressure and lower volume. When the right ventricle is forced to pump blood to the whole body, it develops several maladaptive traits, including overly large muscle and scarring. Eventually, the right ventricle begins to fail and patients will need a heart transplant. "To the best of our knowledge, it's the first time that an injectable biomaterial therapy has been evaluated to mitigate right ventricular heart failure," said Jervaughn D. Hunter, the paper's first author, who hails from Port Gibson, MS and earned his Ph.D. in the Shu Chien-Gene Lay Department of Bioengineering at UC San Diego. In the rodent study, injecting the hydrogel into the right ventricle improved function and allowed the heart to tolerate increased blood pressure and volume. The treatment also slowed down the rate of tissue scarring and maladaptive muscle growth. The hope is that the hydrogel injection will increase the amount of time the patient's heart functions. "This isn't a cure, but our goal is to prolong a patient's life," said Karen Christman, a bioengineering professor at UC San Diego and the paper's corresponding author. The treatment could also dramatically improve the patients' quality of life, allowing better cognitive function and growth. "They might be able to wait until they can get on an adult heart transplant list," said Michael E. Davis, one of the paper's senior authors and director of the Children's Heart Research and Outcomes (HeRO) Center at Children's Healthcare of Atlanta and Professor of Biomedical Engineering at the Georgia Institute of Technology and Emory University School of Medicine. The hydrogel is made from cardiac extracellular matrix that is stripped of the cellular content through a cleansing process; dried and milled into powder form; and then liquefied into a fluid that can be easily injected into the heart. Once it hits body temperature and pH, the liquid turns into a semi-solid, porous gel that encourages the patient's own cells to repopulate areas of damaged cardiac tissue and to improve heart function. Positive results Preclinically, the treament's effects were first seen two weeks after injection. Researchers in Christman's lab prepared the hydrogel with tissue from both the right and left ventricles of the pig hearts. Interestingly, tissues on each side of the heart differ vastly. Hydrogels from either side of the heart improved systolic function-the heart's ability to pump blood. They also reduced heart muscle growth and scaring while prompting arteriole formation and growth. But overall, hydrogel derived from left-ventricle tissue was more effective. That's likely because the hydrogel derived from right-ventricle tissue is richer in type 1 collagen, which may have led to the enhanced inflammatory response seen in the RV hydrogel treated group. The injected hydrogel also affected gene expression, specifically pathways related to cardiac repair, including the development of the circulatory system, muscle structure and vasculature, as well as regulation of immune response and cellular response to oxygen-containing compounds. Next, Children's Healthcare of Atlanta, the children's hospital collaborating with Georgia Tech and Emory will start recruiting for a clinical trial investigating the treatment's efficacy in newborns with hypoplastic left heart syndrome. Funding for the research came in part from the National Institutes of Health National Heart, Lung and Blood Institute.

Longeveron entered 2024 with $5.4 million in cash and equivalents, which is expected to run out by July. Layoffs are in store for employees at both Longeveron and Nicox, although neither company is spelling out how many staff will be affected. Regenerative medicine biotech Longeveron has made the “strategic decision” to discontinue a phase 2 trial of its lead candidate Lomecel-B in aging-related frailty in Japan. The move would result in “related staff reductions” that the company listed as part of “cost-saving measures.” “Longeveron management continues to believe in the potential of Lomecel-B in this disease state and will evaluate options for continued development at a future date,” the company insisted in a full-year earnings report yesterday. The biotech is also hunting for “potential partnerships or other sources of funding” to justify continuing to investigate the drug in Alzheimer’s disease. As recently as December, Longeveron was touting data from a successful phase 2 trial of Lomecel-B in Alzheimer’s, which it claimed “improved cognitive function in multiple measures in a dose-response fashion.” Lomecel-B is made up of medicinal signaling cells from the bone marrow of adult donors that are culture expanded at a cell processing facility. Yesterday’s strategic shake-up means the biotech is now focusing resources on completing enrollment in a phase 2 trial of the living cell therapy in hypoplastic left heart syndrome (HLHS), which CEO Wa’el Hashad described as “our most important near-term value driver.” A quick glance at the company’s finances makes clear why Longeveron is narrowing its focus so significantly. The biotech entered 2024 with $5.4 million in cash and equivalents, which was expected to run out by July. “We are actively seeking financing opportunities to extend our cash runway while taking measures to reduce our cash expenditures as we focus our resources on our primary strategic program in HLHS,” the company said in yesterday’s release. Tight finances are also behind Nicox’s plans to reduce operation costs. The ophthalmology biotech has agreed to an amendment to the repayment of a 16.9 million euros ($14.5 million) debt with Kreos Capital, which will extend the company’s cash runway to November. But, to secure this deal, Nicox had to agree to “reduce its operations in France and Italy” as well as cut operating costs and restructure the company so it’s focused on completing the latest phase 3 Denali trial for glaucoma drug NCX 470. “The additional cash runway and the overall reduction in cash needs gives us the flexibility to advance our core asset and continue partnering and strategic discussions,” Jean-François Labbé, chairman of Nicox’s board of directors, explained in the Feb. 28 release. This means that an undisclosed number of staff tied to Nicox’s home country of France as well as working at its Italian subsidiary will be laid off. “The development team in the U.S., considered essential for the completion of the Denali trial, is not impacted by these changes,” the biotech added. In connection with the downsizing, three members of Nicox’s board will also be departing: Adrienne Graves, Ph.D., Lauren Silvernail and Luzi von Bidder. In a separate announcement on the same day, the biotech revealed that Chief Business Officer Gavin Spencer had been promoted to CEO. Fierce Biotech has contacted both Longeveron and Nicox for more details about how many staff will be affected by the respective workforce reductions but had not received a response at time of publication.