Xenotransplantation

Alfred Joseph Tector, MD

Makana founder Joe Tector, MD, PhD, FACS

In order to meet the high unmet need for people waiting for a life-saving kidney transplant, Makana Therapeutics (originally known as Xenobridge) was founded in 2009 by Joe Tector, MD, PhD, FACS. Dr. Tector, who is also the Director of the Xenotransplant Institute and Surgical Director, Small Bowel and Multivisceral Transplant Program at the University of Miami Medical School, has made it his life’s work to make xenotransplantation a reality. Unlike allotransplantation (human to human), xenotransplantation is the transplantation of living cells, tissues or organs from one species to another.

As a young man, Dr. Tector was inspired by “Baby Fae,” a month-old infant who had received a baboon-heart transplant in 1984. Baby Fae survived the dangerous operation, and her subsequent struggle for life received international attention. She became the first infant subject of a xenotransplant procedure and the first successful infant heart transplant. Though she died within a month of the procedure, she lived weeks longer than any previous recipient of a non-human heart.

Today, for a number or reasons, including size, anatomical, and physiological similarities with humans, the pig is the preferred donor species. Importantly, pigs can be optimized by genetic engineering as a source of cells, tissues, and organs for xenotransplantation.

Dr. Tector and the team at Makana have spent more than a decade developing leading world class expertise in three critical areas needed to make xenotransplantation a future option for patients:


Genetic Engineering

Animal Husbandry and
Advanced Reproduction
of Pigs

Proprietary Transplant
Crossmatch Assays

Genetic Engineering

Makana’s approach to genetic engineering is founded on the “triple knockout” of genes (which was developed in Makana’s laboratories) in the pig donor. While there has been research into adding (instead of removing) genes to the pig donor organ (called transgenes), there is no clear clinical evidence to support any increased efficacy or long-term survival in doing so. Three key carbohydrate pig genes (also called xenoantigens) have been identified by Makana that contribute to antibody mediated rejection. The genes responsible for producing these carbohydrates in the pigs have been removed by modern gene editing techniques to create the Makana Xenoantigen Deficient animal.

Makana’s work to identify and eliminate these xenoantigens has been shown to evade pre-existing and de novo antibodies that are the cause of organ rejection in humans. Makana’s Xenoantigen Deficient organs lack:

 

α-1,3-galactosyltransferase
knockout (GGTA1-KO)

β-1,4-N-acetyl-galactosaminyl
transferase2 knockout
(B4GALNT2-KO)

Cytidine monophosphate-N-acetylneuraminic
acid hydroxylase knockout
(CMAH-KO)

By eliminating these three genes from pigs, it is possible to reduce, and in some cases, eliminate human antibody binding to the pig cells which typically lead to organ rejection or other complications. Makana’s research suggests that the xenoantigen deficient pig will be a suitable kidney donor for as many as 70 percent of kidney failure patients.

Makana’s preclinical work further suggests that continued deletion of xenoantigens will be a successful approach to overcoming the later stages of antibody mediated rejection. Makana’s preclinical data shows >60% 400-day survival rates preclinically, and recipients surviving more than 3 years further confirms this.

Proprietary Cross Match Assay

Makana’s proprietary crossmatch assays will identify patients without pre-existing donor-specific antibodies. This, in turn, will reduce the likelihood of antibody mediated rejection.

Histocompatibility testing with xenoantigen deficient pig cells and human serum from patients on the kidney transplant waitlist suggest that 30% of human patients will have no detectable antibodies against xenoantigen deficient tissues; another 40% of patients will accept xenoantigen deficient tissue with available pre-transplant treatment. In Makana pre-clinical studies, recipients with low anti-pig antibodies achieved the best survival following transplant.

%

Percent of patients who have no detectable antibodies against
xenoantigen deficient tissues

+

%

Percent of Patients who will accept xenoantigen deficient tissue with available
pre-transplant treatment

=

%

70% of total transplant population will be eligible for Makana xenotransplantation

Animal Husbandry

Through gene editing (or genome editing), scientists from Makana and its sister company, Recombinetics, are able to improve the genetics of animals by making precise changes to their DNA. To date, the Makana team is the only company to produce healthy gene-edited animals reliably on a commercial scale.