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Posts Tagged ‘xeno transplantation model’

Xenotransplantation: Pioneering a New Era of Organ Availability

Reporter: Dr. Sudipta Saha, Ph.D.

The 2024 World Medical Innovation Forum (WMIF) spotlighted xenotransplantation as a transformative solution to the organ shortage crisis. By leveraging genetically modified pig organs, this emerging field offers a new source of transplants, expanding life-saving care options.

Key breakthroughs in 2024 have brought new hope for patients, but significant hurdles remain, including immunological rejection. Ongoing research focuses on developing immunosuppressive strategies and enhancing organ compatibility.

Collaboration between scientists, clinicians, and regulatory bodies is essential for xenotransplantation’s future. Experts predict wider clinical availability within the next decade, potentially reshaping organ replacement.

This revolutionary step in organ transplantation holds promise for patients and could redefine the future of transplant care globally. Here’s a comprehensive report covering the research contributions of the panelists from the Xenotransplantation: Game Changing Organ Replacement discussion:

1. Jason Gerberry

Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

Gerberry is a prominent financial analyst with deep expertise in specialty pharmaceuticals and small-to-mid-cap biotechnology firms. His research focuses on investment trends, market dynamics, and the financial viability of innovative medical solutions such as xenotransplantation. At WMIF 2024, he provided insights on how breakthroughs in the field could impact the biotech sector, including the potential for significant investments driven by advancements in gene editing and organ transplantation technologies. Gerberry’s analysis offers critical perspectives on the commercial and economic landscape surrounding xenotransplantation.

2. Joren Madsen, MD, PhD

Director, MGH Transplant Center

Paul S. Russell/Warner-Lambert Professor of Surgery, Harvard Medical School
Dr. Madsen is a leader in transplant surgery and immunology. His research focuses on allograft rejection and immunosuppressive strategies to enhance transplant tolerance. He has been pivotal in advancing clinical transplant practices at Massachusetts General Hospital (MGH) and has made significant contributions to xenotransplantation research by exploring how genetically engineered pig organs could help mitigate immune rejection in human recipients. Madsen’s work is key to translating laboratory findings into clinical applications.

3. Tatsuo Kawai, MD, PhD

Director of the Legorreta Center for Clinical Transplantation Tolerance

A. Benedict Cosimi Chair in Transplant Surgery, MGH

Dr. Kawai specializes in immune tolerance and organ transplantation. His research emphasizes reducing or eliminating the need for lifelong immunosuppressive drugs in transplant patients. He has led groundbreaking clinical trials on tolerance induction, paving the way for the potential acceptance of xenotransplanted organs without rejection. His research is also closely tied to immune tolerance mechanisms and how xenotransplantation can be made safer for human use.

4. Richard Pierson III, MD

Scientific Director, Center for Transplantation Sciences, MGH

Professor of Surgery, Harvard Medical School

Dr. Pierson is renowned for his work in transplantation immunology, focusing on xenotransplantation. His research addresses the fundamental problem of immune rejection of animal organs in human bodies, particularly tackling hyperacute rejection and graft survival. Dr. Pierson has been instrumental in developing strategies to overcome these barriers by modifying pig genetics and using innovative immunosuppressive therapies, which have brought the field closer to clinical application.

5. Leonardo Riella, MD, PhD

Medical Director of Kidney Transplantation, MGH

Harold and Ellen Danser Endowed Chair in Transplantation, Harvard Medical School

Dr. Riella’s research focuses on kidney transplantation and immunosuppressive therapies aimed at improving long-term graft survival. He has been a significant contributor to the field of xenotransplantation, working on improving immune tolerance and understanding how kidneys from genetically modified pigs can function in human bodies without eliciting strong immune responses. His clinical and translational research is critical for the future of xenotransplantation, particularly in renal applications.

Conclusion

These panelists represent leading voices in xenotransplantation, combining their expertise in surgery, immunology, and biotechnology to address the complex challenges of organ transplantation. Their collaborative efforts at MGH and Harvard Medical School are critical in advancing the science of xenotransplantation, bringing it closer to a clinically viable solution for the global organ shortage crisis.

References:

https://www.fda.gov/vaccines-blood-biologics/xenotransplantation

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Author and Curator: Ritu Saxena, Ph.D

Although cancer stem cells constitute only a small percentage of the tumor burden, their self-renewal capacity and possible link with recurrence of cancer post treatment makes them a sought after therapeutic target in cancer. The post on cancer stem cells published on the 22nd of March, 2013, describes the identity of CSCs, their functional characteristics, possible cell of origin and biomarkers. This post focuses on the therapeutic potential of CSCs, their resistance to conventional anti-tumor therapies and current therapeutic targets including biomarkers, signaling pathways and niches.

CSCs Are Resistant to conventional anticancer therapies including chemotherapy, radiotherapy and surgery that are used either alone or in combination. However, these strategies have failed several times to eradicate CSCs resulting in metastasis and relapse, hence, a fatal disease outcome.

The properties of CSCs that contribute to or lead to chemoresistance include:

Quiescent Phenotype

Chemotherapeutic agents target fast-growing cells; however, some CSCs that remain in the dormant or quiescent stage are spared from lethal damage. Later, when the dormant CSCs enter cell cycle, tumor proliferation is stimulated.

Antiapoptosis

Antiapoptotic proteins such as BCL-2 and some self-renewal pathways such as transforming growth factor β, Wnt/ β -catenin or BMI-1 are activated in CSCs. Consequently, DNA damage repair capability of CSCs is enhanced after genotoxic stress or activation of autocrine loops through the production of growth factors like epidermal growth factor (Moserle L, Cancer Lett, 1 Feb 2010;288(1):1-9).

Expression of Drug Efflux Pumps

CSCs express some proteins that have typically been known to contribute to multidrug resistance. The proteins are drug efflux pumps ABCC1, ABCG2 or MDR1. Multidrug resistance-associated proteins (ABCC subfamily) are members of the ATP-binding cassette (ABC) superfamily of transport proteins and act as cellular efflux transporters for a wide variety of substrates, in particular glutathione, glucuronide and sulfate conjugates of diverse compounds.

Radiotherapy is mainly used in breast cancer and glioblastoma multiforme. In glioblastoma multiforme, the properties of CSCs that contribute to radiotherapy resistance is the presence of CD133 marker. CD133+ CSCs preferentially activate DNA damage repair pathway and significantly induced checkpoint kinases that leads to reduced apoptosis in CSCs compared to the CD133- tumor cells (Bao S, Nature, 7 Dec 2006;444(7120):756-60).

Radiotherapy resistance in breast cancer is due to reduced levels of reactive oxygen species in CSCs. In addition, radiation resistance of progenitor cells in an immortalized breast cancer cell line was mediated by the Wnt/β catenin pathway proteins (Diehn M, et al, Nature, 9 Apr 2009;458(7239):780-3; Chen MS, et al, J Cell Sci, 1 Feb 2007;120(Pt 3):468-77).

As mentioned in the previous post on CSCs, CSC targeting therapy could either eliminate CSCs by either killing them after differentiating them from other tumor population, and/or by disrupting their niche. Efficient eradication of CSCs may require the combined ablation of CSCs themselves and their niches. Thus, identification of appropriate and specific markers of CSCs is crucial for targeting them and preventing tumor relapse. Table 1 (adapted from a review article on CSCs by Zhao et al) describes the currently used biomarkers for CSC-targeted therapy (Zhao L, et al, Eur Surg Res, 2012;49(1):8-15).

Table 1

Specific Target Cancer type Marker properties and therapy
Targeting cell markers
CD24+CD44+ESA+ Pancreatic cancer Pancreatic CSCs, elevated during tumorigenesis
CD44+CD24–ESA+ Breast cancer Breast CSCs
EpCAM high CD44+CD166+ Colorectal cancer
CD34+CD38– AML broad use as a target for chemotherapy
CD133+ Prostate cancer and breast cancer 5-transmembrane domain cell surface glycoprotein,also a marker for neuron epithelial, hematopoietic and endothelialprogenitor cells
Stro1+CD105+CD44+ Bone sarcoma
Nodal/activin Knockdown or pharmacological inhibition of its receptorAlk4/7 abrogated self-renewal capacity and in vivo tumorigenicity of CSCs.
Targeting signaling pathways
Hedgehog signaling Upregulated in several cancer types inhibitors: GDC-0449,PF04449913, BMS-833923, IPI-926 and TAK-441
Wnt/β-catenin signaling CML, squamous cell carcinoma Be required for CSC self-renewal and tumor growthinhibitors: PRI-724, WIF-1 and telomerase
Notch signaling Several cancer types An important regulator in normal development, adult stem cell maintenance,and tumorigenesis in multiple organs,inhibitors: RO4929097, BMS-906024, IPI-926 and MK0752
PI3K/Akt/PTEN/mTOR, Several cancer types The pathway is deregulated in many tumors and used to preferentially target CSCsinhibitors: temsirolimus, everolimus FDA-approved therapy for renal cell carcinoma
Targeting CSC Niche
Angiogenesis Niche Colon cancer, breast cancer, NSCLC Inhibitor: bevacizumab results in a disruption of the CSC niche, depleted vasculature and a dramatic reduction in the number of CSCs.
Hypoxia (HIF pathway) Ovarian cancer, lung cancer, cervical cancer Inhibitors: topotecan and digoxin have been approved for ovarian, lung and cervical cancer
Targeting Micro RNA
miR-200 family Inhibits EMT and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2
Let-7 family Regulates BT-IC stem cell-like properties by silencing more than one target
miR-124 Related to neuronal differentiation, targets laminin γ1 and integrin β1.
miR-21 Suppresses the self-renewal of embryonic stem cells

The challenge is to develop an effective treatment regimen that prevents survival, self-renewal and differentiation of CSCs and also disturbs their niche without damaging normal stem cells. In order to evaluate the efficiency of CSC-targeting therapies, in vitro models and mouse xenotransplantation models have been used for preclinical studies. Some potential CSC targeting agents in preclinical stages include notch inhibitors for glioblastoma stem cells and telomerase peptide vaccination after chemoradiotherapy of non-small cell lung cancer stem cells Stem Cells (Hovinga KE, et al, Jun 2010;28(6):1019-29; Serrano D, Mol Cancer, 9 Aug 2011;10:96). In addition, several phase II and phase III trials are currently underway to test CSC-targeting drugs focusing on efficacy and safety of treatment.

Reference:

Bao S, Nature, 7 Dec 2006;444(7120):756-60).

Diehn M, et al, Nature, 9 Apr 2009;458(7239):780-3

Chen MS, et al, J Cell Sci, 1 Feb 2007;120(Pt 3):468-77

Zhao L, et al, Eur Surg Res, 2012;49(1):8-15

Hovinga KE, et al, Jun 2010;28(6):1019-29

Serrano D, Mol Cancer, 9 Aug 2011;10:96

Pharmaceutical Intelligence posts:

http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/ Author and curator: Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/08/15/to-die-or-not-to-die-time-and-order-of-combination-drugs-for-triple-negative-breast-cancer-cells-a-systems-level-analysis/ Authors: Anamika Sarkar, PhD and Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2013/03/07/the-importance-of-cancer-prevention-programs-new-perceptions-for-fighting-cancer/ Author: Ziv Raviv, PhD

http://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/ Reporter: Larry H Bernstein, MD

http://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/ Larry H Bernstein, MD

http://pharmaceuticalintelligence.com/2013/02/14/prostate-cancer-androgen-driven-pathomechanism-in-early-onset-forms-of-the-disease/ Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/15/exploring-the-role-of-vitamin-c-in-cancer-therapy/ Curator: Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2013/01/12/harnessing-personalized-medicine-for-cancer-management-prospects-of-prevention-and-cure-opinions-of-cancer-scientific-leaders-httppharmaceuticalintelligence-com/ Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/ Author and reporter: Tilda Barliya PhD

http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/ Reporter and Curator: Stephen J. Williams, PhD

http://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/ Reporter: Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/10/17/stomach-cancer-subtypes-methylation-based-identified-by-singapore-led-team/ Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/09/17/natural-agents-for-prostate-cancer-bone-metastasis-treatment/ Reporter: Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/ Aviva Lev-Ari, PhD, RN

 

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