First GM pigs for allergies. Could xenotransplants be next?
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First GM pigs for allergies. Could xenotransplants
be next?
The FDA greenlights α-Gal allergy-safe meat, but its makers have organs for transplants in their sights.
T
he first genetically engineered pig
products could soon be coming to
a dinner plate—or pharmacy—near
you. Late last year, the US Food and Drug
Administration (FDA) authorized a facility
in northern Iowa to raise hogs that lack
the gene needed to produce galactose-α-
1,3-galactose (α-Gal), a sugar molecule
found naturally on the surface of porcine
cells. Trademarked under the name ‘GalSafe’,
the pigs could now provide a source of meat
for people who develop tick bite–induced
allergic reactions to the sugar, a condition
known as α-Gal syndrome. Byproducts of
pork production could also be harvested
to make allergy-free pharmaceuticals and
medical implants. The porcine tissue could
help overcome deficiencies in the donor
supply of skin and nerve grafts.
The pigs were never made with any
of those applications in mind, though. In
the early 2000s, following failed attempts
to use unmodified porcine tissue for skin
grafts, pancreatic islet cell transplants and
outside-the-body blood perfusions, David
Ayares and his colleagues at Scotland’s
Gene-edited pigs could solve the human organ transplant shortage. Credit: Pulsar Imagens / Alamy
PPL Therapeutics used a combination
Stock Photo
of recombinant DNA and cloning
technologies—first described in Nature
Biotechnology—to create the pigs as a
source of solid organs for pig-to-human Other xenotransplantation companies Paul Holzer, that six-person, phase 1 trial
xenotransplantation. Soon thereafter, PPL and academic groups hope to build on “truly went better than I could have hoped
spun out Revivicor as a standalone company. Revivicor’s success with the FDA to advance for,” and the company plans to apply for
Revivicor, now a subsidiary of United their own modified pigs and cross-species accelerated approval on the basis of the
Therapeutics, is still angling to transplant transplant products. Some companies are small study’s unpublished results later this
pig kidneys and hearts into human also partnering with Revivicor to develop year. However, it may seek approval with
patients—just not with GalSafe-derived GalSafe-based products for burns and GalSafe skin, rather than the miniature
organs. According to Ayares, who serves of peripheral nerve injury. Axonova Medical, swine hide, now that the Revivicor animals
CSO of Revivicor, the company is hoping for example, uses neurons from GalSafe have passed regulatory muster. (The GalSafe
to launch clinical trials with organs from embryos as the starting material for the pigs are also larger and more fecund than
more elaborately engineered pigs within company’s tissue-engineered nerve grafts. the miniature swine, thus offering more
the next year or two. And he views the Earlier this year, research director Kritika tissue for transplantation.)
landmark approval of first genetically Katiyar and her colleagues reported that Although Revivicor has no plans to
modified pigs as “an important the grafts elicited axon regeneration in rats. commercialize the GalSafe pigs themselves,
stepping-stone” toward that goal. Pig-to-pig studies are planned next. Ayares says his team is looking for more
“All the pieces that went into the FDA Meanwhile, XenoTherapeutics, the licensing opportunities with partners
approval of the GalSafe pigs”—safety company behind the first human trial of interested in selling allergy-free pork or pig
evaluations, environmental impact tissue from a genetically engineered porcine derivatives. For people living with α-Gal
assessments, molecular characterizations of donor, had previously used skin from a syndrome, a group that counts at least
the genetic alteration—“those same pieces different α-Gal-deficient pig—miniature 34,000 individuals in the United States
are going to be required” for approval swine bred by Immerge BioTherapeutics, alone, such food products, if made available
of other engineered pigs intended for a rival to PPL, in the early 2000s—to for purchase, would be a “game-changer,”
xenotransplantation purposes, he says. provide temporary wound closure for says Scott Commins, an allergist at the
The regulatory path is thus better patients with severe burns. According to University of North Carolina-Chapel Hill
defined now—and not just for Revivicor. XenoTherapeutics cofounder and CEO who specializes in treating the condition.
Nature Biotechnology | VOL 39 | April 2021 | 393–400 | www.nature.com/naturebiotechnology 397
news
“The food use is part of the story,” he balance between what’s just right and what’s
Lentiviral vector cleared says, “but in my mind it’s arguably not too much and unnecessary,” Scobie says.
of causing blood cancer as important as the other medical and Building on the foundation of an
implantable uses of the GalSafe pig.” α-Gal-lacking pig, xenotransplantation
Just three weeks after bluebird bio researchers have eliminated more
suspended trials of its bb1111 and a “The food use is part of the pig-specific antigens that were contributing
related gene therapy due to concerns that story, but in my mind it’s to interspecies incompatibilities. Disrupting
its candidates might increase the risk of two genes in particular—cytidine
cancer, the company has reported that arguably not as important monophospho-N-acetylneuraminic
its lentiviral vector is “very unlikely” to acid hydroxylase (CMAH) and β-1,4-N-
as the other medical and acetylgalactosaminyltransferase 2
be the cause. These findings clear the
vector—a relief for the company and the implantable uses of the (B4GALNT2)—proved critical to that effort.
broader gene therapy community. When researchers knocked out CMAH
GalSafe pig.” and B4GALNT2 alongside α-1,3-galactosyl
Bluebird bio’s bb1111 is an ex vivo
Still, any implantable product more transferase (GGTA1), the enzyme
gene therapy candidate that uses
elaborate than, say, a heart valve or responsible for synthesizing the α-Gal
a lentiviral vector called BB305 to
short-term skin graft would need further epitope, cells from the ‘triple knockout’
introduce a hemoglobin gene into
genetic tweaks to prevent organ rejection. (TKO) pigs bound substantially fewer
patient’s blood-producing hemapoeitic
Some say only a couple more knockouts of human antibodies.
stem cells for the treatment of sickle cell
pig carbohydrate antigens should do the “This suggests that organs from
disease. The company halted trials of this
trick. But decades of painfully slow progress TKO animals will be far less prone to
candidate in February after discovering
in large-animal transplantation studies antibody-dependent mediated rejection
that one patient, treated over five years
suggest the elimination of a few pig glycans when transplanted into humans,” says Agnes
ago, had been diagnosed with acute
will be insufficient; more steps, such as Azimzadeh, president of the International
myeloid leukemia (AML) and another
introducing human transgenes or removing Xenotransplantation Association and a
had been diagnosed with myelodysplastic
porcine endogenous retroviruses (PERVs) researcher at the Massachusetts General
syndrome (MDS). These findings
are likely to be needed to protect porcine Hospital’s Center for Transplantation
renewed long-standing concerns over
kidneys, hearts, livers and lungs from injury Sciences in Boston. That TKO construct,
insertional mutagenesis.
in human recipients. she adds, is now the “backbone of any pig”
Further investigations have helped
In the 1990s, following reports that intended for use as an organ donor.
assuage these fears. In the patient
PERVs embedded in the pig genome could On top of that backbone, some
with AML, bluebird bio found that its
take up residence in cultured human cells, teams have also inserted human genes
lentiviral vector, although present in
many researchers and regulatory bodies involved in tempering immune responses
AML blast cells, is inserted into the
worried about the potential infectious to the transplant. These include genes
VAMP4 gene, which has no known role
complications of pig-to-human transplants. encoding components of the complement
in AML or cancer. In the case of the
This was an important concern—one of activation pathway (CD46, CD55 and
other patient, the evidence—which has
many regarding safety— that put the brakes CD59), regulators of platelet coagulation
not included blasts or dysplastic cells
on the field for most of the 2000s. With the (thrombomodulin, tissue factor pathway
in the bone marrow—“is not sufficient
advent of CRISPR–Cas9, Harvard Medical inhibitor and endothelial protein C receptor)
for a diagnosis of MDS,” the company
School geneticist George Church, his former and others with immune-quelling effects
added. Further evaluation of this patient
student Luhan Yang and their colleagues such as heme oxygenase-1 and CD47. Last
is ongoing.
used gene editing to inactivate every single year, for example, scientists at Qihan Biotech
But bluebird bio is not yet fully in
PERV in their first-generation pig. Yang’s and eGenesis—affiliated companies both
the regulatory clear. The company is
logic: “If it’s safer and does not impact the founded by Church and Yang—described
in discussions with the FDA to lift
health” of the pig, she says, why not get rid pigs carrying the triple knockout plus nine
clinical holds from bb1111 and from
of the PERVs? of these human transgenes.
β-thalassemia candidate Zynteglo
But other researchers think that step Revivicor, meanwhile, has engineered
(betibeglogene autotemcel), which uses
is unnecessary to progress to clinical pigs with six human transgenes plus a
the same vector. The EMA approved
xenotransplantation. “We have amassed fourth knockout in the porcine growth
Zynteglo in 2019, but has now launched a
a plethora of data” over the past 20 years, hormone receptor gene, a change designed
safety review of that therapy as well.
and “to date, on no occasion has anyone to prevent organs slated for transplantation
Published online: 12 April 2021 found any evidence that PERVs have caused from getting too large in the donor pigs.
https://doi.org/10.1038/s41587-021-00904-9 infection in human recipients who have been The resulting ‘ten-gene’ pigs will form the
exposed to xenotransplantation,” says Linda basis of the company’s pending clinical
Scobie, a virologist who studies the safety of applications, Ayares says.
xenotransplantation at Glasgow Caledonian Some scientists, though, say that the
University, UK. “PERV is considered to be Revivicor and Qihan/eGenesis pigs are
low risk, and a more pressing concern is overengineered. Christopher Burlak, for
regarding unknown or emerging pathogens.” one, worries about whether the companies
Opinions differ, however, and the genetic can achieve consistent transgene expression
sweet spot for the number of alterations in porcine organs from one transplant
to pig cells sufficient to support safe to the next. “The more complicated the
xenotransplantation remains a matter of genetic engineering of these pigs is, the
intense scientific debate. “We have to find a more difficult it is to produce animals
398 Nature Biotechnology | VOL 39 | April 2021 | 393–400 | www.nature.com/naturebiotechnologynews
reliably,” says Burlak, a xenotransplantation Innovation Program—that offers extensive
researcher at the University of Minnesota in hand-holding by FDA experts for sponsors First-in-class and
Minneapolis. seeking approval of animal cell-based or discovered in India
And as Joseph Tector, an abdominal biotech products. (Revivicor was one of the
A Massachusetts-based biotech with a
transplant surgeon at the University of program’s first participants.) In Carvajal’s
first-in-class bifunctional/trap antibody
Miami Miller School of Medicine, points opinion, “That’s one way of saying to
candidate discovered in India has spun
out, cross-species transplants typically fail industry, ‘We hear you. We think this
out of Biocon, the Bengaluru-based
because of antibody-mediated rejection. technology has a lot of value to it. We want
pharma giant best known for its
“Other issues like coagulation regulation to try to help you navigate this review and
biosimilars and generics. Biocon
and complement regulation—those are approval process.’”
provided the first $40 million in seed
all downstream effects of the antibodies That’s an important message for
funding to launch Bicara Therapeutics,
binding to the cell,” he says. At his company, xenotransplantation veterans like
with the express aim of developing
Makana Therapeutics, a subsidiary of Cooper, who first identified α-Gal as
first-in-class therapeutics for a
Recombinetics, Tector is thus moving ahead the major target of the human immune
global market.
with basic TKO pigs, no transgenes involved. system’s response against pig tissue in the
Bicara’s lead candidate is the
As with human-to-human allotransplants, early 1990s and has collaborated with
EGFR/TGFβ-targeting antitumor agent
he thinks that cross-match methods and the Revivicor team on pig-to-primate
BCA101, which entered phase 1/2 trials
human leukocyte antigen (HLA) typing studies for more than 15 years. “We
in 2020. Approved EGFR-targeted
should be sufficient to allow successful shouldn’t wait for the perfect pig before we
agents including Erbitux (cetuximab)
xenotransplants from TKO pigs. start clinical trials,” he says. Once researchers
have already validated the clinical
Fios Therapeutics is similarly working identify the right immunosuppressive
utility of EGFR blockade in cancer
with TKO pigs, but with one key difference: drug regimens, build the appropriate
treatment. Because BCA101 also blocks
in addition to the triple knockout, the pathogen-free facilities
immunosuppressive TGFβ signaling in
company has incorporated a transgene and design suitable genetically engineered
the tumor microenvironment, Bicara
encoding human CD46, a critical regulator pigs, human testing should follow.
hopes it will achieve better antitumor
of the complement system that contributes “We’re getting close to all of those,” Cooper
activity, a wider therapeutic window
to both innate and adaptive immune says, and the GalSafe approval provides a
and broader therapeutic opportunities.
responses after organ transplantation. “You blueprint to navigate the regulatory thicket.
TGFβ-neutralizing candidates in the
have to control complement early on to
“PERV is considered to be clinic include Sanofi’s SAR439459 and
avoid hyperacute rejection,” says company
Novartis’s NIS793, antibodies that are
founder and CEO Christopher McGregor, low risk, and a more pressing being combined with PD-1/PD-L1
a cardiac surgeon at the University of
blockers for cancer indications.
Minnesota and University College London. concern is regarding unknown Preclinical data suggest that BCA101
Others hope to achieve the
same immune-dampening effects
or emerging pathogens.” has synergistic effects as compared with
the combination of an EGFR-targeted
pharmacologically—although, as surgeon– Outside of the xenotransplantation
therapy and a TGFβ-blocking agent, says
scientist David Cooper, who co-directs the community, however, the approval is likely
Claire Mazumdar, Bicara’s CEO.
University of Alabama at Birmingham’s to have far less of an impact on the animal
“We see this program exemplifying
xenotransplantation program, points out: biotechnology sector writ large. Under the
our strategy, using one arm of a
“The standard immunosuppressive drugs are terms of the FDA’s go-ahead, the Revivicor
bifunctional to target the tumor and
just not up to the task.” Cooper anticipates pigs are limited to one enclosed facility, one
the other arm to provide some kind
that newer, experimental therapies directed herd of no more than 1,000 animals and
of immunomodulatory activity,” says
at the costimulatory protein CD40 or its one abattoir for meat processing—a drop in
Mazumdar. Bicara will tap Biocon’s
ligand, CD154, will allow longer survival of the industry’s bucket considering there are
internal biologics expertise to discover
xenografts. However, clotting complications an estimated 66,000 US swine producers
other novel bifunctional anticancer
have plagued the drug class for decades, churning out more than 72 million pigs
candidates, including two more biologics
and as yet only one experimental agent every year.
that it expects to advance into trials
directed at the CD40 axis has ever Other companies hoping to bring
in 2022. “What Bicara wants to do is
progressed past phase 2 development genetically engineered pigs to the mass
establish that India can be a center for
(dapirolizumab pegol, a humanized market may have to demonstrate similar
R&D innovation,” adds Mazumdar. The
anti-CD154 IgG1 Fab′ fragment from levels of molecular characterization
biotech’s R&D team consists of more than
Brussels, Belgium–based UCB Biopharma to Revivicor’s, but the environmental
50 protein engineers, immunologists
in phase 3 testing for treating lupus). impact assessments will undoubtedly be
and manufacturing experts employed
Despite the many outstanding scientific more onerous—and those stewardship
by Biocon and based in Bangalore, but
uncertainties, Ricardo Carvajal, an expert requirements are “still being designed as
contracted to Bicara. Mazumdar and the
in food law and biotechnology at Hyman, we’re going,” says Elena Rice, CSO of Genus,
rest of the executive management team
Phelps & McNamara in Washington, DC, which has used CRISPR gene-editing to
are located in Cambridge, Massachusetts.
sees a willing partner in the FDA’s Center make pigs resistant to infection with the
for Veterinary Medicine to move the virus responsible for porcine reproductive Published online: 12 April 2021
field forward. Consider the center’s Plant and respiratory syndrome, a costly scourge https://doi.org/10.1038/s41587-021-00906-7
and Animal Biotechnology Innovation of the swine industry.
Action Plan, unveiled in 2018. It includes That regulatory ambiguity is a problem
a pilot project similar to the breakthrough for the entire livestock biotechnology sector,
designation for drugs—the Veterinary says Alison Van Eenennaam, an animal
Nature Biotechnology | VOL 39 | April 2021 | 393–400 | www.nature.com/naturebiotechnology 399news
geneticist at the University of California, typically face little to no scrutiny from Elie Dolgin
Davis. “The lack of regulatory certainty federal agencies in the United States, with Somerville, MA, USA
and the cost [of R&D] has basically dried gene-edited animals “the system is set up
up all investment in this field,” she says. as if you’re dealing with kryptonite,” Van Published online: 12 April 2021
Unlike with CRISPR-edited crops, which Eenennaam says. ❐ https://doi.org/10.1038/s41587-021-00885-9
PLANT BIOTECH
GM chestnut, Sierra Club darling
The first genetically modified chestnut
tree now has a thumbs up from Sierra
Club, an environmental organization that
normally opposes genetic technology.
Sierra Club objections may have
crumbled because, unlike in corporate
industrial agriculture, the purpose
behind genetically engineering the
chestnut tree is to save it. Blight
has all but wiped out the American
chestnut, Castanea dentata. The blight
fungus, Cryphonectria parasitica, was
introduced in the late 1800s with
imported Japanese chestnut nursery
stock. By 1950, four billion American
chestnuts (99.9% of the species) had
died. The transgenic tree, known as
Darling 58, is engineered to resist blight.
The project to restore the American
chestnut to its former glory is ongoing
at the State University of New York’s
College of Environmental Science
and Forestry. Scientists at SUNY American chestnut in flower. Credit: Nick Kurzenko / Alamy Stock Photo
used Agrobacterium to insert a
wheat oxalate oxidase gene into the
wild-type American chestnut. The
oxalate oxidase reduces the blight’s that the trees are protected. SUNY is Lisa Melton
pathogenicity by converting oxalate now seeking official approval before the
from the fungus into hydrogen peroxide transgenic chestnuts can be released Published online: 12 April 2021
and carbon dioxide. Tests so far indicate into the wild. ❐ https://doi.org/10.1038/s41587-021-00903-w
400 Nature Biotechnology | VOL 39 | April 2021 | 393–400 | www.nature.com/naturebiotechnologyYou can also read
