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By targeting a single protein complex, Nuevocor's novel gene therapy approach suppresses the effect of several different mutations that lead to dilated cardiomyopathy.

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Delivering therapies to the heart’s core

7 Apr 2022

Nuevocor, an A*STAR spin-off company, is designing novel therapies to target the genetic causes of heart diseases, bringing basic research to clinical impact.

When a cardiovascular disease diagnosis disrupts the ebb and flow of daily life, individuals find themselves in an unsettling situation. Responsible for nearly one of three deaths in Singapore in 2019, heart disease could also lead to other severe complications like heart failure, malnutrition and fatigue.

One cause of heart failure is dilated cardiomyopathy (DCM), where the left ventricle or heart chamber is enlarged. Because of this increased size, the ventricle walls exert significantly less pressure than usual, resulting in the heart muscle having difficulties pumping enough blood to the rest of the body.

Currently, the standard of care for DCM involves medications or implanted devices, but the most these can do is delay disease progression. The only cure is a heart transplant, but this leaves patients in long waiting lines with no guarantee of finding a matching donor.

Even after a successful operation, a heart transplant leaves patients with life-long effects. Transplant patients must continually use medications like immunosuppressants to reduce the risk of their bodies rejecting the transplanted heart. At the same time however, these drugs weaken the immune system and make patients more susceptible to contracting diseases, infections and even developing certain types of cancer.

As many cases of DCM are traced back to genetic abnormalities, A*STAR spin-off company Nuevocor is developing gene therapies for genetically linked heart diseases, including DCM, to restore cardiac function for good.

Uncovering underlying mechanisms

Among the genetic changes that cause DCM, mutations in the lamin A/C gene (LMNA) manifest in some of the worst ways, posing a greater risk of sudden cardiac death even without other warning signs or prior symptoms. As this type of DCM progresses quickly, about one-third of patients need a heart transplant by age 40, noted Nuevocor CEO Yann Chong Tan.

Tan was previously the Chief Technologist at the NASDAQ-listed biotech company Atreca, which he co-founded based on his PhD work. He was then Chief Innovation Officer at A*STAR's Genome Institute of Singapore (GIS), before joining Nuevocor as he saw an opportunity to use gene therapies to make a difference for this unmet clinical need.

“A significant proportion of the scientific discoveries leading to Nuevocor's solution was underpinned by decades of basic science research," he said, crediting the seminal work of Nuevocor scientific co-founders Colin Stewart and Brian Burke.

The pair, formerly at A*STAR's Institute of Medical Biology (IMB) in the 2010s and now Research Directors at the A*STAR Skin Research Labs (A*SRL), investigated the cellular mechanisms intertwined with LMNA mutations' devastating effects on muscle tissue1. Encoded by LMNA, lamin proteins serve several biological functions such as repairing DNA damage and supporting the nucleus, the cell's control center. They form a basket-like shell called the lamina, which maintains the nucleus' shape and protects it from mechanical stress.

Lamin proteins also interact with the cell's larger filament meshwork called the cytoskeleton via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Christened in Burke’s laboratory, the LINC complex enables the communication between the nucleus and the cell's external world, regulating the internal response to mechanical forces and translating these stimuli into changes in cell behavior and gene expression.

"LMNA mutations disrupt lamin production and assembly of the lamina, compromising its functions and weakening the nucleus' resistance to mechanical forces," Stewart explained. "These forces are particularly significant in tissues like the heart and skeletal muscle, where the cells continuously contract and exert mechanical stress on the nuclei."

From these findings, the team suspected that the LINC complex could hold the answers to addressing LMNA-linked diseases. A significant finding was that using their discovery platform, called PrOSIA, they found that the LINC complex protein SUN1 interacts with lamin A/C.

Mice without the SUN1 gene are essentially normal and long-lived. Stewart’s laboratory developed mice with mutant LMNA gene copies that suffered from DCM and a severely reduced lifespan. Unpublished work from Stewart’s and Burke’s laboratories involving mice with mutations in LMNA and other LINC complex components confirmed the role of the LINC complex, laying the groundwork for Nuevocor's novel approach to treating DCM.

Unlinking a disastrous connection

While gene therapies are a promising technology for treating genetic diseases, conventional methods would be ineffective against LMNA-related DCM. These conventional gene therapies work well only when the patient has mutant copies of a disease gene that result in less or no protein being made. As a result, introducing a working copy of the gene through gene therapy is sufficient to increase or restore protein levels.

In DCM, however, just one mutated copy of LMNA is enough to mask a functional copy delivered through gene therapy. According to Stewart, removing this mutated gene is not viable either, as possessing only one normal copy would also lead to DCM. Moreover, instead of a single hotspot, about 450 culprit mutations are spread throughout the gene, posing considerable difficulties in devising targeted therapies for each of these alterations.

"Nuevocor's unique insight is to deliver another protein that stops the ability of the mutated gene to cause disease, thereby treating DCM," Tan shared.

What sets Nuevocor's gene therapy apart is taking an indirect route to counteract the effects of LMNA mutations, focusing on the LINC complex rather than the nuclear lamina proteins. By targeting the LINC complex, the treatment suppresses several different LMNA mutations with just one reagent.

To achieve this, the A*STAR team used adeno-associated viruses (AAV) as an expression vector—a molecular vehicle for introducing manipulated genes. To help move LMNA gene therapy into the clinic, Nuevocor is relying on the AAV expertise of co-founder Mark Kay from Stanford University and Senior Advisor David Russell, previously Chief Scientific Officer of Universal Cells. Kay and Russell have each invented AAV vectors used in clinical trials and co-founded well-regarded AAV biotech companies.

In AAV, the DNA material is surrounded by a protein shell that enables entry into target cells by latching onto protein receptors, which act as a gate on the cell surface. Besides being relatively easy to produce, AAV vectors pose no risk of severe infectious side effects, making them excellent candidates for delivering interventions directly into human cells.

Nuevocor’s vector contains the code for a negative or mutated version of the SUN1 gene, while the cells' genetic machinery reads these instructions to produce the dysfunctional protein. With its altered structure, the mutant SUN1 protein disrupts the LINC complex, effectively collapsing the bridge between the nucleus and cytoskeleton.

"Disrupting the LINC complex in heart cells physically disconnects the nucleus from the heart cell's cytoskeleton. With this uncoupling, the nucleus is no longer subjected to mechanical stresses exerted when the heart cell contracts," Stewart explained.

Through this AAV-based gene therapy, the team hopes to restore DCM patients' heart functions from their weakened state, counteracting the mutations' disease-causing effects without directly altering the LMNA gene copies themselves2.

On the verge of clinical impact

Nuevocor's scientists are continuously refining their gene therapy procedures by enhancing the AAV technology's specificity in targeting heart cells. Beyond this first treatment for DCM, the team envisions expanding their pipeline of genetic solutions for addressing other cardiomyopathies and giving patients a new lease on life.

Through a unique target discovery platform called PrOSIA, they hunt for more suppressor genes and pathways that can mask the mutations responsible for other heart diseases. By identifying these molecular candidates from rich databases, new treatments can be designed to target and alter these mechanisms, much like how Nuevocor's lead therapy targeted the LINC complex.

"We are searching for other targets that cause heart failure to which we can apply our experience and technologies for developing new treatments," Stewart shared.

In 2021, the team raised US$24 million in Series A funding to advance their innovation beyond the preclinical stage. Amidst Singapore's thriving startup ecosystem and growing biotechnology capacities, such early-stage investments accelerate the journey from research to clinical impact.

For Tan, Nuevocor's success has hinged on years of basic research backed by A*STAR and international collaborations—from understanding the mechanisms underlying these life-threatening conditions to identifying possible drug targets and developing suitable treatment delivery technologies.

"An interdisciplinary approach is needed, so we assembled a strong global team of co-founders and advisors," he said. "We could get everyone to come together because we share a common goal of finding cures for genetic cardiomyopathies."

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1. Burke, B., Stewart, C. The nuclear lamins: flexibility in function. Nature Reviews Molecular Cell Biology 14, 13–24 (2013). | article
2. Chai, R.J., Werner, H., Li, P.Y., Lee, Y.L., Nyein, K.T., et al. Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy. Nature Communications 12, 4722 (2021). | article

This article was made for A*STAR Research by Wildtype Media Group