Organ Health

Using the approach of noninvasive liquid biopsy, Signature’s research includes the study of organ systems and the health of organs themselves. By looking at both the cells that make up the form and function of the organ as well as their effects on the patient’s immune system, we retrieve epigenomic signatures that provide information specific to the patient’s body, such as its response to different treatments.

Our team is actively exploring solutions to the unique complications associated with organ transplants and long-term transplant survival. When a patient receives an organ transplant, new DNA is introduced into their body. Analyzing both the patient’s cell free DNA (cfDNA) and their donor-derived cell free DNA (dd-cfDNA) presents methods that could improve the sensitivity and specificity of post-transplant monitoring.

Renal Health

Renal allografts—also known as kidney transplants—are used to treat patients with end stage renal disease (ESRD). Despite advances in one-year allograft survival, long term survival is still a major concern in the organ transplant space. Premature graft loss generates several detrimental outcomes for the patient, including increased healthcare costs, poor quality of life, and an increased chance of mortality.

Late graft loss is primarily a result of cumulative immune-mediated damage that often goes undetected. The current gold standard for detecting graft rejection is an allograft biopsy, an invasive procedure that is both costly and introduces potential complications for the patient. 1

Organ Health - Renal

46.4%

of kidney transplants are lost by 10 years. 2

23,624

kidney transplants were performed in 2020.3

34.6%

of kidney transplant patients waitlisted between 2015-2017 waited over three years for transplant.3

Our Solution

We are developing technology which utilizes noninvasive diagnostic biomarkers with the goal of identifying patients with subclinical rejection (SCR) and predicting patients who are at risk for acute cellular rejection (ACR). This technique characterizes cell free DNA (cfDNA) methylation signatures in the plasma of kidney transplant recipients.

Our proactive approach to post-transplant monitoring could improve long-term renal allograft survival without the invasiveness of surveillance biopsies, thus providing a higher quality of life for patients.

Lung Health

Lung transplantation is the treatment of choice for patients with end-stage lung disease (ESLD), but while transplant patient survival continues to improve, acute cellular rejection still occurs in up to 50% of patients within the first year following transplantation. If left untreated, ACR can cause significant decline in allograft function.

To detect ACR, lung transplant recipients commonly undergo multiple allograft biopsies for the first two years following the transplant. This invasive surveillance method is associated with various risks and is not always reliable enough to detect ACR for each patient.

Current noninvasive tests for detecting ACR are not sensitive enough to eliminate transbronchial biopsies, and they can not distinguish true allograft rejection from other transplant-related injuries.

Organ Health - Lung

8.9

The median survival rate for patients who surpass one-year lung transplant survival is 8.9 years.4

40%

of deaths beyond the first year of lung transplants are due to allograft failure.5

2,696

people were added to the lung transplant waiting list in 2020.6

Our Solution

Our team aims to employ a noninvasive approach to detecting ACR early by identifying diagnostically relevant signatures in fragments of the patient’s cell free DNA (cfDNA). By focusing on methylation patterns specific to cell type, this method also has the potential to differentiate between allograft rejection and other post-transplant complications. A noninvasive, early detection of ACR could decrease procedure-related risks/costs and improve quality of life for all lung transplant patients.

References

  • 1 Bloom, R. D., Bromberg, J. S., Poggio, E. D., Bunnapradist, S., Langone, A. J., Sood, P., Matas, A. J., Mehta, S., Mannon, R. B., Sharfuddin, A., Fischbach, B., Narayanan, M., Jordan, S. C., Cohen, D., Weir, M. R., Hiller, D., Prasad, P., Woodward, R. N., Grskovic, M., . . . Circulating Donor-Derived Cell-Free DNA in Blood for Diagnosing Active Rejection in Kidney Transplant Recipients (DART) Study Investigators. (2017). Cell-free DNA and active rejection in kidney allografts. Journal of the American Society of Nephrology, 28(7), 2221-2232. https://doi.org/10.1681/ASN.2016091034
  • 2 Hariharan, S., Israni, A. K., & Danovitch, G. (2021). Long-term survival after kidney transplantation. The New England Journal of Medicine, 385(8), 729-743. https://doi.org/10.1056/NEJMra2014530
  • 3 Lentine, K. L., Smith, J. M., Hart, A., Miller, J., Skeans, M. A., Larkin, L., Robinson, A., Gauntt, K., Israni, A. K., Hirose, R., & Snyder, J. J. (2022). OPTN/SRTR 2020 annual data report: Kidney. American Journal of Transplantation, 22(2), 21-136. https://doi.org/10.1111/ajt.16982
  • 4 Chambers, D. C., Perch, M., Zuckermann, A., Cherikh, W. S., Harhay, M. O., Hayes, D., Hsich, E., Khush, K. K., Potena, L., Sadavarte, A., Lindblad, K., Singh, T. P., Stehlik, J., for the International Society for Heart and Lung Transplantation, & International Society for Heart and Lung Transplantation. (2021). The international thoracic organ transplant registry of the international society for heart and lung transplantation: Thirty-eighth adult lung transplantation report — 2021; focus on recipient characteristics. The Journal of Heart and Lung Transplantation, 40(10), 1060-1072. https://doi.org/10.1016/j.healun.2021.07.021
  • 5 Bos, S., Vos, R., Van Raemdonck, D. E., & Verleden, G. M. (2020). Survival in adult lung transplantation: Where are we in 2020? Current Opinion in Organ Transplantation, 25(3), 268-273. https://doi.org/10.1097/MOT.0000000000000753
  • 6 Valapour, M., Lehr, C. J., Skeans, M. A., Smith, J. M., Miller, E., Goff, R., Mupfudze, T., Gauntt, K., & Snyder, J. J. (2022). OPTN/SRTR 2020 annual data report: Lung. American Journal of Transplantation, 22(2), 438-518. https://doi.org/10.1111/ajt.16991