Worldwide First Successful and Reproducable Long-Term Survival up to Half a Year : Completed Preclinical Study with Life-Supporting Orthotopic Pig-to-Baboon Cardiac Xenotransplantation (oXHTx) Fullfilling the ISHLT Prerequisite for Clinical Cardiac Xenotransplantation
(2020) In The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 39(4). p.12-12- Abstract
PURPOSE: Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival of minimal 60% (6 of 10 baboons) in this life-supporting orthotopic pig-to-baboon model (oXHTx), because this is the recommendation of the ISHLT to begin a clinical cardiac XT program. METHODS: We transplanted 8 GalKO/hCD46/hTM transgenic (tg) pig hearts orthotopically into baboons with using a basic immunosuppression consisting of ATG, rituximab, mycophenolate (MMF), cortisone and a... (More)
PURPOSE: Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival of minimal 60% (6 of 10 baboons) in this life-supporting orthotopic pig-to-baboon model (oXHTx), because this is the recommendation of the ISHLT to begin a clinical cardiac XT program. METHODS: We transplanted 8 GalKO/hCD46/hTM transgenic (tg) pig hearts orthotopically into baboons with using a basic immunosuppression consisting of ATG, rituximab, mycophenolate (MMF), cortisone and a costimulation blockade CD40mAb (high dose: 50 mg/kg). To prevent PCXD, we used instead of the crystalloid solution a new non-ischemic 8°C cold perfusion technique with oxygenated erythrocytes. Additional antihypertensive drugs and an mTOR inhibitor (temsirolimus) were applied to inhibit pig xenograft growth and hypertrophy. RESULTS: In comparison to our previous group with crystalloid cardioplegia (Längin et al. Nature. 2018;564:430-433) in this group with cold perfusion preservation (non-ischemic) no PCXD was found. One baboon died of a pancreatitis on day 14, another of sepsis on day 26. By using the antiproliferative therapy, 6 of 8 recipient baboons reached the end of study, were long-term surviving (4 were actively terminated after 90 days according to the guidelines of our government). With special permit two further experiments could be prolonged to half a year and the animals were terminated on day 182 and 195. All baboons lived under excellent physical conditions and no hyperacute rejection or DXR occurred. CONCLUSION: First time in a life-supporting oXHT of multi-tg pig hearts here was a consistent reproduceable long-term survival of 3 - 6 months achieved, which is a major progress after 25 years of research. This is an essential milestone and breakthrough and meets the prerequisite according to the ISHLT to begin a clinical phase I study with patients in terminal heart failure. This paves the way to clinical cardiac XT in the next 2 to 5 years.
(Less)
- author
- organization
- publishing date
- 2020-04
- type
- Contribution to journal
- publication status
- published
- subject
- in
- The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
- volume
- 39
- issue
- 4
- pages
- 1 pages
- publisher
- Elsevier
- external identifiers
-
- scopus:85085635172
- pmid:32464834
- ISSN
- 1557-3117
- DOI
- 10.1016/j.healun.2020.01.1129
- language
- English
- LU publication?
- yes
- id
- bb6009f8-f3dc-49d1-94da-b3f4a2c3bf8a
- date added to LUP
- 2020-06-24 15:07:14
- date last changed
- 2023-08-24 13:38:21
@misc{bb6009f8-f3dc-49d1-94da-b3f4a2c3bf8a,
abstract = {{<p>PURPOSE: Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival of minimal 60% (6 of 10 baboons) in this life-supporting orthotopic pig-to-baboon model (oXHTx), because this is the recommendation of the ISHLT to begin a clinical cardiac XT program. METHODS: We transplanted 8 GalKO/hCD46/hTM transgenic (tg) pig hearts orthotopically into baboons with using a basic immunosuppression consisting of ATG, rituximab, mycophenolate (MMF), cortisone and a costimulation blockade CD40mAb (high dose: 50 mg/kg). To prevent PCXD, we used instead of the crystalloid solution a new non-ischemic 8°C cold perfusion technique with oxygenated erythrocytes. Additional antihypertensive drugs and an mTOR inhibitor (temsirolimus) were applied to inhibit pig xenograft growth and hypertrophy. RESULTS: In comparison to our previous group with crystalloid cardioplegia (Längin et al. Nature. 2018;564:430-433) in this group with cold perfusion preservation (non-ischemic) no PCXD was found. One baboon died of a pancreatitis on day 14, another of sepsis on day 26. By using the antiproliferative therapy, 6 of 8 recipient baboons reached the end of study, were long-term surviving (4 were actively terminated after 90 days according to the guidelines of our government). With special permit two further experiments could be prolonged to half a year and the animals were terminated on day 182 and 195. All baboons lived under excellent physical conditions and no hyperacute rejection or DXR occurred. CONCLUSION: First time in a life-supporting oXHT of multi-tg pig hearts here was a consistent reproduceable long-term survival of 3 - 6 months achieved, which is a major progress after 25 years of research. This is an essential milestone and breakthrough and meets the prerequisite according to the ISHLT to begin a clinical phase I study with patients in terminal heart failure. This paves the way to clinical cardiac XT in the next 2 to 5 years.</p>}},
author = {{Brenner, P. and Reichart, B. and Laengin, M. and Michel, S. and Buchholz, S. and Dashkevich, A. and Wolf, E. and Reimann, K. and Ayares, D. and Hagl, C. and Steen, S. and Abicht, J.}},
issn = {{1557-3117}},
language = {{eng}},
note = {{Conference Abstract}},
number = {{4}},
pages = {{12--12}},
publisher = {{Elsevier}},
series = {{The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}},
title = {{Worldwide First Successful and Reproducable Long-Term Survival up to Half a Year : Completed Preclinical Study with Life-Supporting Orthotopic Pig-to-Baboon Cardiac Xenotransplantation (oXHTx) Fullfilling the ISHLT Prerequisite for Clinical Cardiac Xenotransplantation}},
url = {{http://dx.doi.org/10.1016/j.healun.2020.01.1129}},
doi = {{10.1016/j.healun.2020.01.1129}},
volume = {{39}},
year = {{2020}},
}