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Powerful gene therapies to reverse heart or liver failure and dementia

Novel gene therapy works to reverse heart failure, says recent studies described in news releases, Long-lasting gene therapy benefits advanced heart failure patients November 19, 2013 and Novel gene therapy works to reverse heart failure November 13, 2013. Preclinical testing shows SUMO-1 gene therapy shrinks an enlarged heart, improves heart function, and blood flow

New research on life-saving gene therapies about which seniors are curious.
New research on life-saving gene therapies about which seniors are curious.
Photo credit: Mount Sinai. This is the study's principal investigator Roger J. Hajjar, M.D., who developed a gene therapy approach. Long-lasting gene therapy benefits advanced heart failure patients.

The November 19, 2013 news release notes that the recent study results show clinical event rates in gene therapy patients are significantly lower three years later compared to those patients receiving placebo. Also, patients experienced no negative side effects following gene therapy delivery at three-year follow-up.

Powerful gene therapies to reverse heart failure

Researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai have successfully tested a powerful gene therapy, delivered directly into the heart, to reverse heart failure in large animal models. The new research study findings, published in November 13, 2013 issue of Science Translational Medicine, is the final study phase before human clinical trials can begin testing SUMO-1 gene therapy. SUMO-1 is a gene that is "missing in action" in heart failure patients.

"SUMO-1 gene therapy may be one of the first treatments that can actually shrink enlarged hearts and significantly improve a damaged heart's life-sustaining function," says the study's senior investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai, according to the November 13, 2013 news release, Novel gene therapy works to reverse heart failure. "We are very eager to test this gene therapy in our patients suffering from severe heart failure."

Heart failure remains a leading cause of hospitalization in the elderly

It accounts for about 300,000 deaths each year in the United States. Heart failure occurs when a person's heart is too weak to properly pump and circulate blood throughout their body.

Dr. Hajjar is already on a path toward approval from the Food and Drug Administration to test the novel SUMO-1 gene therapy in heart failure patients. When it begins, the clinical trial will be the second gene therapy treatment designed to reverse heart failure launched by Dr. Hajjar and his Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

The first trial, named CUPID, is in its final phases of testing SERCA2 gene therapy. Phase 1 and phase 2a trial results were positive, demonstrating substantial improvement in clinical events

In that trial, a gene known as SERCA2 is delivered via an inert virus — a modified virus without infectious particles. SERCA2 is a gene that produces an enzyme critical to the proper pumping of calcium out of cells. In heart failure, SERCA2 is dysfunctional, forcing the heart to work harder and in the process, to grow larger.

The virus carrying SERCA2 is delivered through the coronary arteries into the heart during a cardiac catheterization procedure. Studies show only a one-time gene therapy dose is needed to restore healthy SERCA2a gene production of its beneficial enzyme. But previous research by Mount Sinai discovered SERCA2 is not the only enzyme that is missing in action in heart failure.

A study published in Nature in 2011 by Dr. Hajjar and his research group showed that the SUMO-1 gene is also decreased in failing human hearts. But SUMO-1 regulates SERCA2a's activity, suggesting that it can enhance the function of SERCA2a without altering its levels. A follow-up study in a mouse model of heart failure demonstrated that SUMO-1 gene therapy substantially improved cardiac function.

This new study tested delivery of SUMO-1 gene therapy alone, SERCA2 gene therapy alone, and a combination of SUMO-1 and SERCA2

In large animal models of heart failure, the researchers found that gene therapy delivery of high dose SUMO-1 alone, as well as SUMO-1 and SERCA2 together, result in stronger heart contractions, better blood flow, and reduced heart volumes, compared to just SERCA2 gene therapy alone.

"These new study findings support the critical role SUMO-1 plays for SERCA2 function, and underlie the therapeutic potential of SUMO-1 gene replacement therapy for heart failure patients," reports Dr. Hajjar, in the news release.

Also, according to Dr. Hajjar, the time it took investigators to translate their basic laboratory findings to successful preclinical studies was very short. "The key reason for this translational medicine speed is the outstanding infrastructure we have in the Cardiovascular Research Center at Mount Sinai, where we are able to replicate human heart failure models to test our novel gene therapies," says Dr. Hajjar. "I think this is a really very unique example of rapid translation of a promising medical therapy from an initial discovery to pre-clinical trials."

Other study investigators are all from Icahn School of Medicine at Mount Sinai. They include co-first authors Lisa Tilemann, MD, and Ahyoung Lee, PhD. Additional co-authors are Kiyotake Ishikawa, MD, Jaume Aguero, MD, Kleopatra Rapti, PhD, Carlos Santos-Gallego, MD, Erik Kohlbrenner, BS, Kenneth Fish, PhD, and Changwon Kho, PhD.

The study was supported by a National Institutes of Health grants (RO1 HL117505, HL119046, HL093183, P20HL100396), and a NHLBI Program of Excellence in Nanotechnology (PEN) Award (Contract # HHSN268201000045C). Dr. Hajjar is the scientific cofounder of the company Celladon, which plans to develop AAV.SERCA2a gene therapy for the treatment of heart failure. All other authors declare no competing financial interests.

The November 19, 2013 news release, " Long-lasting gene therapy benefits advanced heart failure patients " discusses the recent Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai where researchers report promising long-term follow-up results for its single dose AAV1/SERCA2a gene therapy in advanced heart failure patients

Researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai explained, according to the news release, that the long-term benefits of a single dose of their gene therapy AAV1/SERCA2a in advanced heart failure patients on Nov. 19 at the American Heart Association Scientific Sessions 2013.

The new long-term follow-up results from their initial Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) clinical trial found a one-time, high-dose injection of the AAV1/SERCA2a gene therapy results in the presence of the delivered SERCA2a gene up to 31 months in the cardiac tissue of heart failure patients.

In addition, study results show clinical event rates in gene therapy patients are significantly lower three years later compared to those patients receiving placebo

Also, patients experienced no negative side effects following gene therapy delivery at three-year follow-up. "This study shows AAV1/SERCA2a gene therapy has long-lasting and beneficial effects for congestive heart failure patients allowing us to block the downward spiral of patients with severe heart failure, " says principal investigator Roger J. Hajjar, MD, according to the November 19, 2013 news release. Hajjar is the Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine at Icahn School of Medicine at Mount Sinai, who developed the gene therapy approach.

The gene therapy uses a modified adeno-associated viral-vector derived from a parvovirus

The one-time gene therapy is injected through the coronary arteries of heart failure patients using catheters. It works by introducing healthy SERCA2a genes into cells. The delivery of the SERCA2a gene produces SERCA2a enzymes, which helps heart cells restore their proper use of calcium.

SERCA2a is an enzyme critical for proper pumping of calcium in calcium compartments within cells. SERCA2a dysfunction or reduced expression occurs in patients with heart failure. When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. This contributes to an enlarged heart in heart failure patients.

Previously, CUPID 1 study results showed the gene therapy to be clinically safe and effective for over 12 months with improved heart function status and left ventricular function, along with a significant decrease in recurrent cardiovascular events

CUPID 1 was the first-in human clinical gene therapy randomized, double-blind study which enrolled 39 patients with advanced heart failure. "AAV1/SERCA2a gene therapy has been proven to be a safe and effective therapeutic intervention for advanced heart failure," says Dr. Hajjar, according to the November 19, 2013 news release. "Our long-term results support the potential use of AAV1/SERCA2a gene therapy as a new important additional tool for treating and managing advanced heart failure patients."

This study was presented as an Oral Session (Abstract 10667): Long Term Follow-up of Patients with Advanced Heart Failure Following a Single Intracoronary Infusion of AAV1/SERCA2a

In addition, on Nov. 19, 2013 Dr. Hajjar also presented at the AHA Scientific Sessions 2013 a Plenary talk entitled, "How the Postgenome Era Will Change the Practice of Cardiology" and discussed his work on targeted gene therapy for human heart failure.

In his Plenary talk, Dr Hajjar presented his new findings just published in the journal Science Translational Medicine on Nov. 13 that show delivery of small ubiquitin-related modifier 1 (SUMO-1), an important regulator of SERCA2a, in preclinical heart failure models improves cardiac contractility and prevents left ventricular dilatation — two major aspects of heart failure. According to Dr. Hajjar, the transition of this SUMO-1 gene therapy from pigs to humans seems likely in the short-term. Also, Dr. Hajjar revealed that development of novel cardiotropic vectors may render cardiovascular gene therapy easier and less-invasive in the near future.

Dr. Hajjar is the scientific cofounder of the company Celladon, which is developing AAV1/SERCA2a gene therapy for the treatment of heart failure. He holds equity in Celladon and receives financial compensation as a member of its advisory board.

Cell transplantation for Alzheimer's disease, a new approach to treating this ailment

Combination of cell transplantation and gene therapy for Alzheimer's disease, is a new approach to treating this health condition, say researchers in a new study, "Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy, " recently published in the journal Neural Regeneration Research (Vol. 8, No. 33, 2013), which you can read online as a PDF file article.

There was no significant difference in cell viability between cells transfected with siBACE1-2 plasmid and those that were untransfected, say the scientists, according to the December 24, 2013 news release, "Combination of cell transplantation and gene therapy for Alzheimer's disease."

What that means is that in the recent study published in Neural Regeneration Research (Vol. 8, No. 33, 2013), Prof. Feng Li and team from Zhongshan School of Medicine, Sun Yat-sen University in China, synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein (Aβ) production, and introduced it into the pSilenCircle vector to construct a short hairpin (shRNA) expression plasmid against the BACE1 gene. You also can check out the website, Neural Regeneration Research.

Reducing the brain's amyloid beta (Aβ) protein production with gene therapy

Researchers transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing Aβ protein production. This technique combining cell transplantation and gene therapy will open up novel therapeutic avenues for Alzheimer's disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.

You can read the full study online, "Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy " by Zhonghua Liu, Shengliang Li, Zibin Liang, Yan Zhao, Yulin Zhang, Yaqi Yang, Minjuan Wang, Feng Li (Department of Neurobiology and Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China)

Liu ZH, Li SL, Liang ZB, Zhao Y, Zhang YL, Yang YQ, Wang MJ, Li F. Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy. Neural Regen Res. 2013;8(33):3095-3106. For more information sea NRR online and check out that study.

How to turn skin cells into mature liver cells that flourish on their own

Scientists at the Gladstone Institutes and the University of California, San Francisco, have made an important breakthrough. The researchers have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure. Research results of the new study, "Mouse liver repopulation with hepatocytes generated from human fibroblasts" are published online February 23, 2014 in the journal Nature.

Scientists transform skin cells into functioning liver cells in a new study. The joint Gladstone Institutes - University of California, San Francisco (UCSF) study highlights novel reprogramming method. This study offers new hope for treating liver failure.

The power of regenerative medicine now allows scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and even neurons. However, a method to generate cells that are fully mature—a crucial prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), have made an important breakthrough: they have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure.

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue.

The difference now is that the Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

These results offer new hope for the millions of people suffering from, or at risk of developing, liver failure—an increasingly common condition that results in progressive and irreversible loss of liver function

At present, the only option is a costly liver transplant. So, scientists have long looked to stem cell technology as a potential alternative. But thus far they have come up largely empty-handed. "Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells," explained Dr. Ding, one of the paper's senior authors, according to the February 23, 2014 news release, "Scientists transform skin cells into functioning liver cells."

Sheng Ding also is a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. Ding explained in the news release, "However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn't always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase."

Endoderm cells mature into many of the body's major organs such as the liver

This research, which was performed jointly at the Roddenberry Center for Stem Cell Research at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, involved using a 'cocktail' of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body's major organs—including the liver.

"Instead of taking the skin cells back to the beginning, we took them only part way, creating endoderm-like cells," added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one of the paper's lead authors, according to the news release. "This step allowed us to generate a large reservoir of cells that could more readily be coaxed into becoming liver cells."

Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation

"The cells began to take on the shape of liver cells, and even started to perform regular liver-cell functions," said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper's other lead author, according to the news release. "They weren't fully mature cells yet—but they were on their way."

Now that the team was encouraged by these initial results in a dish, they wanted to see what would happen in an actual liver. So, they transplanted these early-stage liver cells into the livers of mice. Over a period of nine months, the team monitored cell function and growth by measuring levels of liver-specific proteins and genes.

The transplanted cells were becoming functioning liver cells

Two months post-transplantation, the team noticed a boost in human liver protein levels in the mice, an indication that the transplanted cells were becoming mature, functional liver cells. Nine months later, cell growth had shown no signs of slowing down. These results indicate that the researchers have found the factors required to successfully regenerate liver tissue.

"Many questions remain, but the fact that these cells can fully mature and grow for months post-transplantation is extremely promising," added Dr. Willenbring, according to the news release. Holger Willenbring is the associate director of the UCSF Liver Center and the paper's other senior author. "In the future, our technique could serve as an alternative for liver-failure patients who don't require full-organ replacement, or who don't have access to a transplant due to limited donor organ availability."

Other scientists who participated in this research include UCSF researchers Jack Harbell, MD, also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet, PhD. Funding was provided by the following: the California Institute for Regenerative Medicine, the National Institutes of Health, the German Academic Exchange Service, and the Society of University Surgeons.

The "Gladstone Institutes" is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of California, San Francisco.