PE R S PE C T IV E
Disclosure forms provided by the authors
Progress toward Pig-to-Human Xenotransplantation
Progress toward Pig-to-Human Xenotransplantation
Richard N. Pierson III, M.D.​​
This article was published on May 14, 2022,
are available at NEJM.org.
From the Leonard Davis Institute of Health
Economics and Perelman School of Medi-
cine, University of Pennsylvania, Philadel-
phia (R.M.W.); the Department of Public
Health Sciences, University of Chicago,
Chicago (R.T.K.); the Department of Health
Care Policy, Harvard Medical School, Bos-
ton (D.C.G.); and the Department of Health
Policy, Vanderbilt University School of
Medicine, Nashville (D.G.S.).
T he recent announcements that
genetically modified pig kid-
neys survived for more than 2 days
after being attached to the circu-
lation of three brain-dead hu-
mans — two at New York Uni-
versity (NYU; see Montgomery
et al., pages 1889–98) and one at
the University of Alabama at Bir-
mingham (UAB)1 — and that a
life-supporting pig-to-human heart
transplantation was performed at
the University of Maryland (UMD)
have made headlines. Commen-
tators have pronounced these ad-
vances “a huge breakthrough”
and “a watershed moment.”
And indeed, xenotransplanta-
tion carries the promise of an
unlimited supply of readily avail-
able, safe, optimally functioning
organs. Although organs from
nonhuman primates have exhib-
ited life-supporting function in
human recipients of kidney, liver,
and heart transplants, in the 1990s
concern that endogenous retro-
viruses might cause contagious
infection in humans led to a mor-
atorium on such transplantations
in the United States and many
other countries. The very limited
supply of chimpanzees (the most
biologically compatible and size-
appropriate potential source ani-
mal), logistic barriers to creating
certifiably “safe” primate donors,
n engl j med 386;20
Nursing Home Financing, Payment, and Oversight
tion. February 3, 2022 (https://www​.­k ff​.­org/​
at NEJM.org.
1. Institute of Medicine. Improving the
quality of care in nursing homes. Washing-
ton, DC:​National Academies Press, 1986.
2. Office of the Inspector General. Nursing
homes. January 18, 2022 (https://oig​.­h hs​
.­gov/​­reports​-­and​-­publications/​­featured​-­topics/​
­nursing​-­homes/​­).
3. Chidambaram P. Over 200,000 residents
and staff in long-term care facilities have
died from COVID-19. Kaiser Family Founda-
and substantial ethical concerns
steered the field toward domesti-
cated species.
Pigs soon became the consen-
sus domesticated option, given
their size at maturity, their favor-
able innate breeding characteris-
tics, and the availability of clon-
ing and related reproductive
technologies to propagate known
essential and potentially protec-
tive genetic features. Preclinical
testing of organs from cloned
pigs in nonhuman primates gen-
erated a large body of data for
predicting their efficacy and safe-
ty in human use. In light of the
recent clinical cases, taking stock
of progress in xenotransplanta-
tion can help us set realistic ex-
pectations for clinical adoption
of this promising technology.
The NYU transplantations dem-
onstrated that pig kidneys can
maintain a relatively normal out-
ward appearance and continue to
produce urine for at least a few
days, presumably without major
adverse effects on recipients’ phys-
iology, although the UAB report
was less encouraging in this re-
spect. Numerous studies in non-
human primates have predicted
that a pig kidney from which a
principal species-specific antigen
has been removed by genetic en-
gineering (with the galactose-­
nejm.org May 19, 2022
­policy​-­watch/​­over​-­200000​-­residents​-­and​-­staff​
-­in​-­long​-­term​-­care​-­facilities​-­have​-­died​-­f rom​
-­covid​-­19/​­).
4. National Academies of Sciences, Engi-
neering, and Medicine. The national im-
perative to improve nursing home quality.
National Academies Press, 2022 (https://
www​.­n ationalacademies​.­org/​­e vent/​­0 4​-­06​
-­2022/​­report​-­release​-­webinar​-­t he​-­n ational​
-­imperative​-­to​-­improve​-­nursing​-­home​-­quality).
DOI: 10.1056/NEJMp2203429
Copyright © 2022 Massachusetts Medical Society.
Nursing Home Financing, Payment, and Oversight
alpha-1,3-galactose [alpha-gal]
epitope removed by means of
alpha-1,3-galactosyltransferase
gene knockout [GTKO]) — the
type of organ used at NYU —
will function for a few days in
the majority of cases, at least in
the absence of high titers of anti-
bodies to non–alpha-gal epitopes.2
However, since GTKO kidneys
express at least two other carbo-
hydrate antigens that are recog-
nized by preformed human anti-
pig antibodies, they may not be
optimal for transplantation; triple-
knockout (TKO) pig kidneys —
which also lack the two other
dominant targets of humans’
preformed anti-pig antibodies,
N-glycolylneuraminic acid and Sda
— as in the UAB and UMD pro-
cedures, may be more clinically
useful. More important, since the
native kidneys remained in place
in the NYU cases, the UAB pro-
cedural approach can tell us more
about the xenograft’s contribu-
tion to renal function.
The pig used at UAB not only
had undergone TKO modification
but also was “designed” to ad-
dress other barriers: vigorous
innate and adaptive immune re-
sponses; interspecies incompati-
bilities in molecular interactions
involving the coagulation path-
ways, among others; and the risk
1871
PERS PE C T IV E
of causing adventitious infection.3,4
Binding of human anti-pig anti-
bodies is greatly reduced in TKO
xenografts. Damage associated
with residual anti-pig antibodies
or with anti-donor antibodies
generated after transplantation
can be attenuated by expression
in the pig of one or more human
complement pathway regulatory
proteins (hCPRPs).
Recipients of GTKO.hCPRP or
TKO.hCPRP organs typically ex-
hibit thrombodysregulation with-
in the organ xenograft (throm-
botic microangiopathy) and in the
recipient’s circulation (consump-
tive coagulopathy). Such dysregu-
lation is refractory to intensified
immunosuppression and is seen
even when there is partial adap-
tive immunologic tolerance in the
T-cell compartment. This “delayed
xenograft rejection” appears to
be preventable by expression of
one or more human thromboreg-
ulatory genes, including the genes
that encode human thrombo-
modulin (hTBM), endothelial cell
protein C receptor, and human
CD39 (hCD39). Innate immune
injury by macrophages and natu-
ral killer cells is triggered by the
absence of hCD47 or HLA-E “self-
recognition” inhibitory pathways,
and such injury should be pre-
vented by expression of these hu-
man molecules by the pig organ.
TKO pigs designed to have at
least one of these three additional
categories of protective gene
“knock-ins” (complement, coagu-
lation, and self-recognition) have
been produced and are being
evaluated in preclinical models.
It’s clear that experimental
costimulation-based immunosup-
pression using antibodies to block
CD40 or CD154 is superior to
any regimen tested to date in pri-
mate recipients that depends on
the calcineurin or mammalian
target of rapamycin inhibitors —
1872
Progress toward Pig-to-Human Xenotransplantation
conventional immunosuppressive
drugs that are the mainstay of
current clinical allotransplanta-
tion.5 Although none of these
costimulation-blocking antibod-
ies are currently approved for a
clinical indication, several have
recently progressed to phase 2
trials in autoimmune diseases,
which suggests that they may well
prove safe in transplant recipi-
ents. With either anti-CD40 or
anti-CD154 monoclonal antibod-
ies, kidneys from pigs of at least
three different genotypes provid-
ed life-supporting function in mon-
keys or baboons that consistently
surpassed 6 months and occa-
sionally even 3 years.3 Two re-
search groups have reported oc-
casional survival of recipients of
orthotopic heart transplants be-
yond 6 months with similar well-
tolerated drug regimens; a Munich
team achieved consistent survival
beyond 3 months using relative-
ly “simple” GTKO.hCD46.hTBM
hearts.4
Supported by these encourag-
ing results, multiple groups are
preparing to request regulatory
approval for clinical trials. The
Food and Drug Administration
(FDA) says it’s receptive to con-
sidering a clinical xenotransplan-
tation trial that uses both an ex-
perimental drug regimen and a
multiply modified, genetically en-
gineered pig organ, as long as
the investigators provide scien-
tific justification for both.
What about potential infec-
tious risks? The FDA and other
national regulatory agencies have
provided clear guidance on this
front: they expect any pig organ
used clinically to come from a
donor animal, and preferably a
herd, that is certifiably free of
known pathogenic bacterial, viral,
and protozoal organisms. Exten-
sive work suggests that pig endog-
enous retroviruses are unlikely to
n engl j med 386;20 nejm.org May 19, 2022
prove clinically important in hu-
mans; should infection occur,
with or without symptoms, the
recipient could be treated with
antiretroviral drugs developed for
HIV that have exhibited potent in
vitro activity against replication
of pig endogenous retroviruses.4
Moreover, CRISPR-Cas9 gene-edit-
ing technology has been used to
efficiently delete these retrovi-
ruses, providing proof of princi-
ple that, if necessary, they could
be eliminated from pig strains
intended for clinical use.
Practically, source pigs will
need to be “derived into” a zoo-
notically isolated facility at birth.
Although initial clinical trials
may be conducted using cloned
animals raised in such a facility,
commercially viable production at
scale will require establishing
breeding herds. Until a pig phe-
notype and treatment regimen
have been confirmed to be clini-
cally viable (at which point the
costs will be covered by or on be-
half of individual recipients), the
cost of maintaining swine in a
clinical-grade barrier facility will
remain an obstacle to clinical
translation.
The limited clinical experience
to date may make it hard to ob-
tain informed consent for initial
xenotransplantation trials. But I
believe ethical equipoise can be
achieved for carefully selected pa-
tients whose particular situations
make participation in a xenograft
trial a reasonable alternative, de-
spite the uncertain prospects. For
example, some patients with high
levels of antibodies against anti-
gens in other humans but not
against pig antigens might wel-
come the chance to avoid the
predictably long wait for a com-
patible human kidney. The cur-
rent evidence seems to justify
moving toward clinical trials of
kidney and heart xenotransplan-
PE R S PE C T IV E Progress toward Pig-to-Human Xenotransplantation

tation. FDA approval of clinical proceed first, because recipients From the Division of Cardiac Surgery, De-
partment of Surgery, and the Center for
trials supported by Investigation- could probably return to dialysis Transplantation Sciences, Massachusetts
al New Drug applications (which in the event of graft failure. The General Hospital, and Harvard Medical
are distinct from compassionate recent cases provide an opportu- School — both in Boston.
use exemptions) will require defin- nity to educate health care pro- 1. Porrett PM, Orandi BJ, Kumar V, et al.
ing a pig phenotype fessionals and the public about First clinical-grade porcine kidney xeno-
An audio interview transplant using a human decedent model.
with Dr. Pierson
and treatment regi- xenotransplantation’s potential, as Am J Transplant 2022 January 20 (Epub
is available at NEJM.org men that consistently well as its public health risks and ahead of print).
result in life-support- financial implications. Increased 2. Pierson RN III, Dorling A, Ayares D, et al.
Current status of xenotransplantation and
ing xenograft function in nonhu- public awareness and full trans- prospects for clinical application. Xenotrans-
man primates, brain-dead humans, parency during clinical trial plan- plantation 2009;​16:​263-80.
or brave patients consenting to ning and execution will be need- 3. Adams AB, Lovasik BP, Faber DA, et al.
Anti-C5 antibody tesidolumab reduces early
participate in additional pilot com- ed to generate support for organ antibody-mediated rejection and prolongs
passionate use experiments. xenotransplantation trials. But survival in renal xenotransplantation. Ann
Given the field’s enormous po- with iterative improvements now Surg 2021;​274:​473-80.
4. Längin M, Mayr T, Reichart B, et al.
tential benefits to human health further informed by recent clini- Consistent success in life-supporting por-
and current estimates of the like- cal experimentation, general dis- cine cardiac xenotransplantation. Nature
ly risks to recipients and society semination of organ xenotrans- 2018;​564:​430-3.
5. Pierson RN III, Fishman JA, Lewis GD,
at large, initial clinical kidney and plantation has begun to seem et al. Progress toward cardiac xenotrans-
heart xenotransplantation trials like a feasible near-term goal. plantation. Circulation 2020;​142:​1389-98.
could begin within a few years. Disclosure forms provided by the author DOI: 10.1056/NEJMp2118019
A kidney trial will presumably are available at NEJM.org. Copyright © 2022 Massachusetts Medical Society.
Progress toward Pig-to-Human Xenotransplantation

Only Halfway There with Sudden Infant Death Syndrome

Only Halfway There with Sudden Infant Death Syndrome

Richard D. Goldstein, M.D., Hannah C. Kinney, M.D., and Alan E. Guttmacher, M.D.​​

F or more than 10% of pediat-

ric deaths in the United States,
a specific cause of death is never
established, despite mandated au-
topsies and investigations when
any child dies unexpectedly. Most
of these deaths occur among ba-
bies and are attributed to SUID
(defined by the Centers for Dis-
ease Control and Prevention as sud-
den unexpected infant death), the
leading cause of death among in-
fants between 1 month and 1 year
of age in high-income countries.
SUID is a category of pediatric
death encompassing various diag-
noses that were once considered
sudden infant death syndrome
(SIDS), and SIDS remains its ma-
jor component. Since the 1990s,
the perception of SIDS has shift-
ed from a medical mystery to a
sleep accident, and public health
campaigns warning about risk fac-
tors in the infant-sleep environ-
ment have supplanted the search
for medical causes. Evidence sug-
gests, however, that renewed ef-
forts to identify biologic causes
are required to further reduce
unexplained infant deaths.
Few experts would argue with
the current focus on prevention,
which is based on associations
between infant-sleep practices and
SIDS rates in multiple countries.
Beginning in the 1970s, SIDS
mortality more than doubled in
the Netherlands after physicians
advocated for prone placement of
infants for sleep; mortality then
dropped after caregivers were ad-
vised to return to the traditional
practice of placing babies on
their backs.1 An association be-
tween infant sleep practices and
SIDS was first identified by sev-
eral researchers in the late 1980s.
In 1991, the New Zealand Cot
Death Study, which was initiated
because Maori infants had one of
the world’s highest-reported SIDS
rates, showed an odds ratio for
SIDS of 3.53 associated with sleep-
ing in the prone position.2 In the
United States, SIDS rates dropped
by half during the Back to Sleep
campaign in the 1990s. Still, rates
of unexplained deaths among in-
fants have remained largely un-
changed since 1996 in the United
States (where the current rate is
90.1 per 100,000 live births; see
graph) and elsewhere.
During the past several dec-
ades, the concept of SIDS as a
preventable suffocation event oc-
curring in normal infants has
taken hold. Public health cam-
paigns, which typically rely on
simple, clear messages, empha-
size addressing sleep position and

n engl j med 386;20 nejm.org May 19, 2022 1873

Reproduced with permission of copyright owner. Further reproduction
prohibited without permission.