Developing New Biomarkers To Detect Early Organ Transplant Failure

Stan Rose, PhD President & CEO of Transplant Genomics Dr. Rose is also a kidney transplant recipientMedicalResearch.com Interview with:
Stan Rose, PhD
President & CEO of Transplant Genomics
Dr. Rose is also a kidney transplant recipient

MedicalResearch: What is the background for these studies? 

Dr. Rose: The studies by the founding scientists of Transplant Genomics (TGI) presented at the World Transplant Congress (WTC) 2014 represent years of work by our scientific founders and their collaborators at leading institutions in their search for  minimally invasive diagnostic and monitoring tools enabling earlier and more accurate detection and characterization of graft injury in organ transplant recipients.

In kidney transplant recipients, for example, current methods consist of tracking creatinine levels and periodic direct assessment of grafts through biopsies. But by the time creatinine levels are elevated, more than 50% of kidney function may be lost. Biopsies, considered the gold standard for assessing graft status, are invasive, risky, unsuited for serial monitoring, and yield inconclusive results as often as 30% of the time.

Transplant Genomics is addressing the need for better monitoring by developing a peripheral blood test for genomic biomarkers of transplant graft status to detect early signs of graft injury, differentiate between actionable causes and enable optimization of immunosuppressive therapy.

MedicalResearch: Can you explain what peripheral blood gene expression profiling is?

Dr. Rose: Recent studies have identified a number of genes that are differentially expressed in both the blood of kidney transplant recipients and kidney biopsies themselves, as conditions which lead to dysfunction begin and progress. Gene expression profiling, in this case using microarrays, allows the simultaneous analysis of expression levels of a large number of genes, and correlation of such multi-gene expression level “signatures” with specific phenotypes of interest. It can be done using peripheral blood samples, which are easy to collect and noninvasive compared to collecting tissue biopsies.

MedicalResearch: What are the main findings of these reports?

Dr. Rose: The studies presented at the World Transplant Congress represent the foundation for the company’s development of genomic tests for transplant graft status:

Classification of Graft Status

  • The study Molecular Phenotyping of Kidney Biopsies by Global Gene Expression Tightly Correlates with Histology Phenotypes and Long-term Outcomes1 compared gene expression profiling data from biopsy tissue against biopsy results in 292 patients. The authors showed that gene expression profiling has a predictive accuracy of 90–94% for acute rejection, acute dysfunction no rejection, chronic allograft nephropathy and transplant excellence samples, when compared to histology-documented phenotypes.
  • Discovery of Peripheral Blood and Biopsy-Based Molecular Classifiers in Brazilian Kidney Transplant Patients2 validated biopsy molecular phenotypes created with a US population in an independent cohort of significantly different racial/ethnic backgrounds. Predictive accuracies ranged from 87% to 94%.

Subclinical Acute Kidney Rejection

A major challenge in kidney transplant management is detecting subclinical acute rejection (SCAR), defined as histologic rejection even though the patient’s serum creatinine readings are normal. In Molecular Signature in the Peripheral Blood for Sub-clinical Acute Kidney Rejection,3 the researchers showed that peripheral blood gene expression profiling can correctly classify kidney transplant patients with subclinical acute rejection, acute rejection and transplant excellence. The discovery of this signature represents a true breakthrough in efforts to develop predictive tests that can be used for routine serial monitoring of kidney transplant recipients.

Gene Expression Profiling in Liver Transplants

Blood and Biopsy mRNA Expression Signatures Can Distinguish Major Causes of Graft Injury in Liver Transplant Recipients4 demonstrated that genomic signatures of specific types of liver graft injuries can be identified from both blood and biopsy tissue. The signatures are able to distinguish acute rejection in liver transplant recipients from other major causes of graft injury, such as hepatitis C virus recurrence and alternative causes with high predictive accuracy. This discovery paves the way for a noninvasive differential diagnostic test that can be used to monitor liver graft status and guide treatment decisions when problems are detected.

MedicalResearch: What should clinicians and patients take away from this investigation?

Dr. Rose: A genomics approach to organ transplant testing can yield more accurate and more complete diagnostic information, providing new, noninvasive tools for transplant monitoring with the ability to detect organ injury earlier, even in advance of dysfunction. Transplant Genomics’s first test will be a blood test used to routinely monitor kidney transplant recipients, indicating when treatment or biopsy is required.

MedicalResearch: What is happening next as a result of these studies?

Dr. Rose: A large ongoing, multi-center study, funded by the National Institutes of Health through the Clinical Trials in Organ Transplant (CTOT) consortium and other groups, is underway involving prospective serial sample collection from 300 kidney transplant recipients and 300 liver transplant recipients. The results of this work will provide further independent validation of our signatures and support our efforts to move these peripheral blood tests from bench to bedside.

We are also working with several major transplant centers on clinical trials aimed at establishing clinical utility and cost effectiveness under various scenarios, the results of which will support efforts to drive test adoption by clinicians and reimbursement by payers. Commercial testing services will be offered through an independent CLIA laboratory we are establishing with plans to be operational early in 2015.

 References:

  1. Kurian SM, Modena B, Friedewald J, et al. Molecular phenotyping of kidney biopsies by global gene expression tightly correlates with histology phenotypes and long-term outcomes. Poster presentation A495 at World Transplant Congress, July 27, 2014.
  2. Ventura C, Kurian SM, Gelbart T, David-Neto E, Salomon DR. Discovery of peripheral blood and biopsy-based molecular classifiers in Brazilian kidney transplant patients. Poster presentation A523 at World Transplant Congress, July 27, 2014.
  3. Friedewald J, Kurian S, Levitsky J, et al. Molecular signature in the peripheral blood for sub-clinical acute kidney rejection. Presentation at World Transplant Congress, July 30, 2014.
  4. Levitsky J, Salomon D, Kurian S, et al. Blood and biopsy mRNA expression signatures can distinguish major causes of graft injury in liver transplant recipients. Presentation at World Transplant Congress, July 31, 2014.

 

 

 

Last Updated on October 9, 2014 by Marie Benz MD FAAD