Prediction of post-heart transplant primary graft dysfunction using exosome proteins

This technology predicts a patient’s risk of developing primary graft dysfunction (PGD) after a heart transplant by measuring levels of exosome proteins such as kallikrein (KLKB1), to improve risk stratification, organ allocation, and post-operative care.

Unmet Need: Reliable method for determining risk of developing primary graft dysfunction

Primary graft dysfunction (PGD), defined as severe ventricular dysfunction with no discernible etiology occurring within 24 hours post-transplant, is the most common cause of death in the month following heart transplant. PGD represents a significant expenditure to the medical system as the mechanical ventilator support needed to keep a patient with PGD alive is costly. Since the cause of PGD is unknown, there is currently no way of knowing whether a patient will develop PGD. A method capable of analyzing these factors and accurately predicting the risk of PGD prior to transplant using reliable biomarkers would be highly valuable.

The Technology: Pre-transplant blood test to predict the risk of primary graft dysfunction

It has been hypothesized that certain circulating factors pre-dispose heart transplant recipients to the development of primary graft dysfunction (PGD). This technology uses proteomics analysis of exosomal proteins derived from patient sera prior to heart transplant to identify biomarker signatures specific to patients at risk for post-transplant primary graft dysfunction. This blood test assesses the levels of a panel of exosome proteins, notably plasma kallikrein (KLKB1), to predict PGD with high accuracy prior to transplant.

This technology was derived from serum samples of patients seen at three institutions. This technology has been validated in transplant patients seen at Columbia University.

Applications:

• Pre-heart transplant blood test to risk-stratify patients for primary graft dysfunction (PGD)
• Identification of exosome-derived biomarkers that predispose to PGD after other organ transplant (e.g. lung, liver)
• Identification of molecular targets to prevent or treat post-heart transplant PGD
• Use of the kallikrein-kinin system as a diagnostic and therapy for PGD

Advantages:

• Non-invasive test requiring only a blood sample
• Unbiased Monte Carlo cross-validation (MCCV) model to the risk of primary graft dysfunction (PGD)
• Reduced cost and incidence of PGD
• High-throughput analysis for identification of drug targets against PGD
• Inflammation and immune pathway enrichment to characterize the pre-transplant signature predictive of PGD and other post-transplant risks

Lead Inventor:

Barry Fine, M.D., Ph.D.

Patent Information:

Patent Pending (WO/2022/060842)

Related Publications:

• Giangreco NP, Lebreton G, Restaino S, Farr M, Zorn E, Colombo PC, Patel J, Soni RK, Leprince P, Kobashigawa J, Tatonetti NP, Fine BM. “Alterations in the kallikrein-kinin system predict death after heart transplant” Sci Rep. 2022 Aug; 12(1): 14167

• Giancrego NP, Lebreton G, Restaino S, Farr MJ, Zorn E, Colombo PC, Patel J, Levine R, Truby L, Soni RK, Leprince P, Kobashigawa J, Tatonetti NP, Fine BM. “Plasma kallikrein predicts primary graft dysfunction after heart transplant” J Heart Lung Transplant. 2021 Oct; 40(10): 1199-1211

• Kennel PJ, Saha A, Maldonado DA, Givens R, Brunjes DL, Castillero E, Zhang X, Ji R, Yahi A, George I, Mancini DM, Koller A, Fine B, Zorn E, Colombo PC, Tatonetti N, Chen EI, Schulze PC. “Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection” J Heart Lung Transplant. 2018 Mar; 37(3): 409-417.

• Giangreco N, Chen E, Zorn E, Restaino S, Colombo PC, Tatonetti N, and Fine B. “Identification of Novel Primary Graft Dysfunction Biomarkers Using Exosome Proteomics” Circulation. 2017 Jun; 136: A19311.

Tech Ventures Reference:

• IR CU18316

• Licensing Contact: Kristin Neuman