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Can we use Gene & Cell Therapy to treat Cardiac fibrosis?

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Antonio Carusillo
Antonio Carusillo Dec 13, 2020
How can we exploit Gene and Cell therapy to addres fibrosis?

Given the incredible development in novel gene and cell based apporaches, can we think about possible strategies to addess not only Cancer or Immunedeficiencies but also other life threatening conditions like Cardiac fibrosis?

What is Fibrosis?

Cardiac fibrosis is a process of seeing a pathological remodeling of the extracellular matrix (ECM), which can lead to abnormalities in matrix composition and quality, affecting proper heart muscle function. Initially, ECM deposition is a protective mechanism, and it can support wound healing and tissue regeneration. However, excessive and continuous ECM deposition, particularly collagen type I secretion, leads to impaired tissue function due to stiffness and reduced flexibility of the cardiac muscle itself.
Cardiac fibrosis is a scarring event in the cardiac muscle that is characterized by an increased collagen type I deposition as well as cardiac fibroblast activation and differentiation into myofibroblasts. These pathological changes lead to an increased matrix stiffness and lead to abnormalities in cardiac function.
Fibrotic scars of the cardiac muscle most commonly occur after myocardial infarction; however, various other conditions are promoting cardiac fibrosis such as hypertensive heart disease and diabetic hypertrophic cardiomyopathy.

What are CAR T Cells and can we exploit them?

Chimeric Antigen Receptor (CAR) T cells are T lymphocytes engineered to be redirected toward a specific target against which they mount a potent immune response. CART cells have been successfully used to fight against blood malignancies with two CART cells drugs – Yescarta and Kymriah - approved in the USA and Europe. Furthermore, a great effort is being also put to develop CART cells against solid tumors, and recently, on this platform, we have also discussed how CART cells may be used as senolytics to target senescent cells in the attempt to ameliorate the age-related phenotype.
CAR T cells are engineered to express a specific receptor on the surface which, upon contact with the antigen, triggers the immune response.
For these reasons, we can think of identifying a specific receptor that may enable the design of CART cells specific for fibrotic tissues.

A mouse model suggests the feasibility of CART as a possible therapeutic in fibrotic tissues

Similar to what has been done in the development of the senolytic CAR T cells, a research group analyzed the transcriptome of 238 left ventricular tissue samples of human heart transplant donors and recipients. They identified the fibroblast-specific genes that were upregulated in the myocardium of patients with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) compared to the control, non-failing donor hearts. They picked what they defined as Fibroblast activation protein (FAP) because it showed the greatest fold change in the expression (upregulation) in either DCM or HCM when compared to controls. The idea, as you may imagine is to come up with an antigen that is expressed only by the intended target as they won’t avoid “off-targeting” by the CART Cells.
After the identification of FAP, they generated these so-called FAP CART Cells and tested them in a mouse characterized by heart tissue scarring. The researchers could not only observe a reduction in the fibrotic tissue but also a partial rescue of both systolic and diastolic cardiac function in injured mice treated with FAP CAR T cells that was not seen in the controls .

Some question marks:

Although these results provide a proof-of-concept for the possibility of targeting cardiac fibrosis in mice with engineered T cells and immuno-therapy, there are some questions that should be addressed:
  • Is FAP the best target or can we target other antigens?
  • Can FAP also be a target in other heart tissue injury cases besides HCM and DCM?
  • Can we identify rather multiple antigens to make the CART even more specific so that the immune response is triggered only if both the antigens are present?
  • Should this type of CART have a safety-switch to “kill” the CART cells if any side-effect is observed after administration?

A broader question:

Based on the CAR T design rationale, what other condition we may target with CART cells? Meaning a non-physiological situation caused by faulty cells?

On the same line may we think about targeting fibrotic muscle cells as a way to ameliorate ageing-related muscle wasting?

[1]Svenja Hinderer, Katja Schenke-Layland, Cardiac fibrosis – A short review of causes and therapeutic strategies, Advanced Drug Delivery Reviews, Volume 146, 2019, Pages 77-82, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2019.05.011.

[2]Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019)

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Creative contributions

Long-term therapeutic benefits of CAR-T therapy

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Jamila
Jamila Dec 14, 2020
Hi Antonio.
Great session! CAR-T therapy is definitely promising.

The fact that researchers observed a decrease in fibrotic tissue and improved cardiac function in the injured mice is brilliant and could have clinical applications in humans one day. However, I do wonder whether using CAR-T therapy has long-term therapeutic effects? Or would there be a need for multiple treatment doses with the CAR-T therapy? I guess what I'm wondering is whether removing the dysfunctional cells could prevent further dysfunctional cells from arising in the future.

Cells produce collagen for structural support in the heart. However, when this is excessively made, it can cause cardiac fibrosis. I'm not sure why the cells produce excess collagen in the first place, but it would be important to find out why.

[1]Cowling, Randy T., et al. "Mechanisms of cardiac collagen deposition in experimental models and human disease." Translational Research 209 (2019): 138-155.

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