Gene Editing and Next-Gen Antibodies: Breakthroughs in Xenotransplantation

In a significant leap forward for organ transplantation, recent advancements in gene editing and immunosuppression are paving the way for xenotransplantation—the transplantation of animal organs into humans. This development offers hope for addressing the critical shortage of donor organs, with potential to revolutionize treatment for end-stage organ failure.

The Organ Shortage Crisis

The United States faces a dire organ shortage, with approximately 20 people dying daily while waiting for transplants. The kidney transplant waitlist alone includes about 90,000 patients, yet only 25,000-30,000 transplants are performed annually. Mike Curtis, CEO of eGenesis, a biotech company developing genetically engineered pig organs, notes that the true need far exceeds these numbers, with roughly 450,000 patients on dialysis.

Gene Editing: A Game-Changer for Xenotransplantation

Companies like eGenesis and Revivicor, a subsidiary of United Therapeutics, are at the forefront of developing genetically modified pig organs for human transplantation. These modifications aim to overcome the primary hurdles of xenotransplantation:

1. eGenesis's approach involves three classes of gene edits:

   • Inactivating retroviruses in the pig genome
   • Eliminating antigens responsible for hyper-acute rejection
   • Introducing human regulatory genes for various immune functions

2. Revivicor's method includes editing 10 genes to limit organ growth and prevent rejection, inflammation, and blood clot formation.

Recent human trials have shown promise. In March 2024, a 62-year-old man with end-stage kidney disease received an eGenesis-edited porcine kidney. Although the patient died two months later, Massachusetts General Hospital stated the transplant was not the cause. In 2023, two patients received genetically edited pig hearts from Revivicor, with mixed outcomes.

Next-Generation Antibodies: The Key to Preventing Rejection

While genetic modifications help, experts believe next-generation costimulatory blockade antibodies could be crucial in preventing organ rejection. The most significant pathway involves the interaction between CD40 and CD154 proteins.

Eledon Pharmaceuticals is leading this effort with tegoprubart, an anti-CD40L antibody currently in Phase II trials for traditional kidney transplantation and preclinical testing for xenotransplantation. CEO David-Alexander Gros describes tegoprubart's mechanism as "immunomodulation" rather than immunosuppression, potentially replacing nephrotoxic calcineurin inhibitors commonly used in transplants.

Other companies exploring similar approaches include:

• Novartis: Testing frexalimab in multiple sclerosis
• UCB and Biogen: Assessing dapirolizumab pegol in systemic lupus erythematosus
• Tonix Pharmaceuticals: Developing TNX-1500 for organ rejection prevention

Challenges and Future Outlook

Despite these advancements, significant challenges remain. Adam Griesemer from NYU Langone's xenotransplant research team emphasizes the need for stronger immunosuppression in xenotransplantation compared to human-to-human transplants.

Large-scale clinical trials are crucial to understand the true efficacy of anti-CD40L antibodies in humans. As both eGenesis and United Therapeutics move towards traditional clinical trial pathways, the industry eagerly anticipates more controlled data and clearer regulatory pathways.

While xenotransplantation shows immense promise, with potential to eliminate organ waitlists and even dialysis, researchers caution that the field is still in its early stages. With only about seven human recipients of xenotransplants to date, compared to the annual need of 130,000 organs, there is still a long road ahead in making this revolutionary approach a widespread reality.