Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model

Zhuo Wang; Shuangquan Jiang; Shouqiang Li; Weidong Yu; Jianfeng Chen; Dandan Yu; Chen Zhao; Yingjie Li; Kai Kang; Ranran Wang; Mengmeng Liang; Mingyuan Xu; Yanmei Ou; Piyu Li; Xiaoping Leng; Jiawei Tian; Thomas R-Porter

doi:10.1016/j.biomaterials.2020.120366

Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model

Biomaterials. 2020 Dec:263:120366. doi: 10.1016/j.biomaterials.2020.120366. Epub 2020 Sep 6.

Authors

Zhuo Wang¹, Shuangquan Jiang², Shouqiang Li¹, Weidong Yu², Jianfeng Chen³, Dandan Yu², Chen Zhao², Yingjie Li⁴, Kai Kang⁵, Ranran Wang², Mengmeng Liang², Mingyuan Xu², Yanmei Ou², Piyu Li², Xiaoping Leng⁶, Jiawei Tian⁷, Thomas R-Porter⁸

Affiliations

¹ Department of Ultrasound Imaging, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Heilongjiang Province, Harbin, 150086, China.
² Department of Ultrasound Imaging, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
³ Laboratory Animal Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
⁴ Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
⁵ Department of Cardiac Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
⁶ Department of Ultrasound Imaging, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Heilongjiang Province, Harbin, 150086, China. Electronic address: xpleng@ems.hrbmu.edu.cn.
⁷ Department of Ultrasound Imaging, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Heilongjiang Province, Harbin, 150086, China. Electronic address: jwtian2004@163.com.
⁸ Department of Cardiology, University of Nebraska Medical Center, Omaha, NE, NE 68198, USA.

PMID: 32950914
DOI: 10.1016/j.biomaterials.2020.120366

Abstract

Background: Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model.

Methods and results: Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001).

Conclusions: Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression.

Key words: Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.

Keywords: Acute rejection; Galectin-7; Heart transplantation; Microbubble; RNA interference.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Galectins
Genetic Therapy
Heart Transplantation*
Microbubbles
Pharmaceutical Preparations*
Rats
Rodentia

Substances

Galectins
Pharmaceutical Preparations