Record number of gene-therapy trials, despite setbacks - Nature
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Credit: Science Picture Co / Alamy Stock Photo
Record number of gene-therapy trials, despite
setbacks
The recent failure of a gene therapy for Huntington’s disease was devastating for patients, but researchers
remain optimistic.
Carrie Arnold
F
or decades, Claudia Testa has longed This is why Testa and so many others 1/2 trials showing it was safe and that it
to tell her patients with Huntington’s in the Huntington’s community were lowered huntingtin levels. So when Roche
disease that she has a treatment avidly following the progress of a phase announced in March 2021 that it was pulling
for them. The neurologist at Virginia 3 trial for tominersen. The drug is an the plug on the phase 3 trial of tominersen,
Commonwealth University could prescribe antisense oligonucleotide (ASO), a short, Testa and others were devastated.
medications to help control the psychiatric single-stranded piece of DNA designed to “This resets the timeline,” she says.
symptoms of the deadly neurodegenerative bind to a specific mRNA target. Tominersen, The field was hopeful that 2021 would
condition, and to manage its characteristic developed by Ionis Pharmaceuticals and be the first year they would have a real
jerking and writhing, but when it came licensed to Roche, binds to the mRNA disease-modifying therapeutic, Testa says.
to drugs that could slow the disease’s encoding the mutant huntingtin protein “And now we’re back to infinity.”
progression, Testa had nothing. Neither did and targets it for degradation by the An interim analysis of the trial data
anyone else. cell. Tominersen sailed through phase showed no difference between the patients
1312 Nature Medicine | VOL 27 | August 2021 | 1312–1315 | www.nature.com/naturemedicine
news feature
who received an intrathecal infusion of
tominersen every 16 weeks and those who
received the placebo. Worse, the patients
who received tominersen every 8 weeks
appeared to be getting sicker than the
control participants.
“They made the only decision they could
possibly make. They had to stop,” Testa says.
At the same time, a smaller phase 1/2
trial of an ASO for treating patients with
Huntington’s disease by Wave Therapeutics
(from whom Testa receives consulting
fees) was also shuttered after preliminary
results showed the compound failed to
decrease levels of mutant huntingtin. The
company is now throwing its support
behind a newer, potentially more effective
ASO. As the Huntington’s community
reeled from back-to-back blows, two other
biotechnology companies—Cambridge,
Massachusetts–based Voyager Therapeutics,
and uniQure in Amsterdam—moved
forward with gene-therapy trials that use
adeno-associated virus (AAV) vectors to Adenovirus particles as seen by transmission electron microscopy (digital coloring). Credit: BSIP
deliver microRNAs that are designed SA / Alamy Stock Photo.
to reduce toxic levels of mutant
huntingtin protein.
This rollercoaster ride is emblematic
of the gene-therapy field’s recent growing Children’s Hospital of Philadelphia at every type of tissue, even non-dividing
pains, although safety concerns and lack the time. cells. Crucially, AAV, unlike adenovirus,
of efficacy have not stopped the explosive The problem was not the new gene rarely elicits a strong immune response,
growth in trials. Clinicaltrials.gov lists nearly to be delivered but instead the vector so researchers could give patients the high
5,000 gene-therapy trials, and more than 100 delivering the gene. Finding a way to doses of the virus that are often needed
trials of ASOs from around the world, more safely and effectively introduce a novel to get the correct gene into an adequate
than ever before. But the long-term safety of gene (or gene-editing system) into the number of cells.
some of these therapies remains unclear. body’s cells continues to be the lynchpin of “It’s amazing that, for the most part,
any gene-therapy endeavor, says Jennifer you can actually get away with these high
Everything stopped Hamilton, a postdoctoral fellow in the lab of doses. It tells you how benign this vector is,”
In the late 1990s, gene therapy seemed just Nobel Prize–winner Jennifer Doudna at the Herzog says.
around the corner. Scientists had nearly University of California, Berkeley. Over time, more safety information
finished sequencing the human genome, “Delivery is the key thing that needs to was gathered from preclinical trials, and
and genetic engineering allowed them to be considered for these types of approaches,” regulators gained experience evaluating this
transform viruses that caused diseases she says. information, says Peter Marks, Director
such as the common cold and even AIDS The adenovirus vector’s ability to elicit a of the Center for Biologics Evaluation and
into delivery vehicles for life-saving robust immune response is partly the reason Research at the FDA. After more than a
gene therapies. The idea that researchers vaccinologists have used adenovirus to build decade, gene therapy seemed poised to
could cure even the deadliest of human the ChAdOx1 vaccine against COVID-19. take its first hesitant steps forward. This,
diseases did not sound so far-fetched. Then But this immunogenicity has led researchers along with the advent of CRISPR-based
everything went horribly wrong. to turn to other viruses to deliver gene gene-editing tools, meant that at first a few
In 1999, 18-year-old Jesse Gelsinger therapy. The fact that scientists would trials launched under nervous eyes, then
received an injection of an adenovirus vector continue to rely on viruses was no surprise, hundreds. The field seemed unstoppable.
that carried a corrected copy of his mutated according to Hamilton. “Viruses are well Then, yet again, everything went
gene encoding ornithine transcarbamylase, evolved to get genes from outside the cell to horribly wrong.
which caused a rare X-linked liver inside,” she says.
disorder. The adenovirus vector sparked an Instead of adenovirus, they began Too high a dose
overwhelming immune response that led experimenting with engineered lentiviruses On 6 May 2020, alerts from Nicole Paulk’s
to his death four days later. The US Food such as HIV and with AAVs. “AAVs were mobile phone woke the gene-therapy
and Drug Administration (FDA) placed an a huge advance. It changed the whole expert at the University of California, San
immediate clinical hold on gene-therapy landscape of gene therapy,” says Mark Francisco, several hours before dawn.
trials, and overnight, the field went from Sands, a gene-therapy expert at Washington Colleagues had questions about the death of
sizzling to frigid. University School of Medicine in St. Louis. a participant in the ASPIRO gene-therapy
“Everything just seemed to stop,” says AAV continues to be the most popular trial by Audentes Therapeutics. The Bay
Roland Herzog, an immunologist at Indiana vector partly due to its multiplicity of Area biotechnology company (now part
University, who was a postdoctoral fellow at serotypes, which are able to infect nearly of the Japanese pharmaceutical company
Nature Medicine | VOL 27 | August 2021 | 1312–1315 | www.nature.com/naturemedicine 1313news feature
Astellas Pharma) had developed a gene A. In February, the team at bluebird bio picked up by tests in non-human primates,
therapy for the rare neuromuscular disease announced two cases of acute myeloid Sabatino says, because these animals develop
X-linked myotubular myopathy. They leukemia, as well as one incidence of an immune response to the human gene
delivered a very high dose of AAV: 3 × 1014 myelodysplastic syndrome (a diagnosis later therapy. This means their bodies fight off the
vector genomes per kilogram of body revised to transfusion-dependent anemia), virus and its accompanying genetic payload,
weight. The boy subsequently died as a in participants in its trial of LentiGlobin so monitoring generally lasts for only a
result of sepsis. gene therapy for sickle-cell disease. And in few months.
Seven weeks later, a second boy who had late April 2021, Adverum Biotechnologies “This is the value of long-term animal
received the same high dose of the same announced that a participant in its trial models for follow-up. You can’t track a
AAV gene therapy died. On 20 August, so for diabetic macular edema had developed monkey for several months and expect to
did a third boy—all three died of sepsis. To vision loss in the dosed eye. find a clonal expansion,” she says.
Paulk, the deaths were a stark warning about The FDA’s Center for Biologics
the potential dangers of high-dose AAVs. Unexpected integration Evaluation and Research, which oversees
“I don’t think anyone expected such Despite these setbacks, and despite COVID- gene-therapy trials and approvals, is aware
a profound response that couldn’t be 19, the number of new gene-therapy trials of the potential for long-term issues with
controlled,” she says. has sped up in the past year. Sands wonders gene therapy, Marks says. The FDA is now
The question on her mind—on everyone’s if this is wise. recommending 15 years of follow-up
mind—was whether the field was having After Gelsinger’s death, gene-therapy in its draft gene-therapy guidance
another ‘Jesse Gelsinger moment’. As in the experts began to rely on AAVs as the vector for industry.
Gelsinger case, scientists had noted severe of choice. This small virus seemed like the “We have to have safety of these products,
toxicity in preclinical tests when non-human workhorse the field was looking for. But and that’s why we are here at FDA, to make
primates were given high doses of the even as AAV was being hailed as the savior sure that this is done safely,” Marks says.
therapy. High-dose AAVs had also caused of gene therapy, Sands had noticed some Alison Bateman-House, a bioethicist at
liver and immune system toxicities in animal long-term safety issues. New York University, agrees that long-term
models and in humans given gene therapy Sands found a hepatocellular carcinoma animal studies are needed. Without knowing
for Duchenne muscular dystrophy. in several neonatal mice treated with the full magnitude of potential risk,
“Back when the original events occurred an AAV-based gene therapy, used to Bateman-House says, patients
at the turn of the millennium, we did not treat a metabolic disorder. After Sands cannot provide true informed consent for
have the same amount of experience at published his findings in 2001, however, clinical trials.
FDA,” Marks says. “The scientific knowledge his conclusions were questioned because “We’re really flying blind with this,”
and regulatory maturation have given us previous trials had dosed older mice with she says.
more confidence. It’s why these deaths didn’t AAVs without an apparent problem.
stop the field like it did in 2000.” “There were a lot of companies that Where do you want it?
In December 2020, the FDA lifted its were springing up and there were a lot of Sands and Sabatino remain optimistic
clinical hold on the ASPIRO trials. “The people’s reputations on the line,” Sands about the promise of AAVs and other gene
exact biological mechanism that led to the says. “Everyone said these vectors were therapies. To Paulk, the challenge will
patients’ deaths has not been conclusively benign and here I come along and say wait a be designing better recombinant vectors
determined,” says Edward Conner, Astellas minute. There was enormous pushback.” with improved tropism and decreased
Gene Therapies Site Lead. “Within the Six years of arduous bench work finally immunogenicity so that patients need less
comprehensive review, Astellas has not yielded the specific sites where the AAV vector and have a reduced chance of a severe
identified clinical evidence, either direct or vector had integrated itself into the mouse immune reaction.
indirect, that immune responses contributed genome. Sands and colleagues discovered At Affinia Therapeutics, based in
to the liver injury.” that the viruses had inserted themselves Waltham, Massachusetts, Chief Scientific
A detailed analysis of the company’s into a 6-kilobase region on chromosome Officer Charles Albright says that the
internal findings was published. Still, 12, altering the expression of host genes company is working to engineer precisely
scientists held their breath, and fears grew and leading to tumorigenesis. To Sands, these types of improved vectors. One vector
as serious adverse events appeared in this highlights the need for long-term safety has 32 times more RNA expression, which
other gene-therapy trials. In December studies on AAV-based gene therapy so the allows use of a reduced dose; another vector
2020, Amsterdam-based uniQure reported field can move forward safely. was tweaked both to steer it away from the
that one person in its phase 3 trial of an “I am a huge proponent of AAV therapy. liver and again to steer it towards muscle.
AAV5-based therapy for hemophilia B had But my concern has always been that if “This is very advantageous,” says
developed hepatocellular carcinoma (in [integration] is a problem for human gene Albright. “To detarget the liver and
March 2021, an independent investigation therapy, it should have been studied in a increase uptake into muscle—this specific
cleared the vector of any role). A uniQure systematic way for the past 20 years,” he says. combination will be very powerful if we can
spokesperson said that detailed analysis “If we don’t understand how integration is translate it to non-human primates.”
of the patient’s liver tissue revealed happening, we can’t re-engineer the AAVs to Ongoing safety concerns about
a precancerous state due to several make them safer.” AAV-based gene therapies have led some
pre-existing conditions. Sabatino agrees. Her work found that scientists rethink how gene therapy
At the University of Pennsylvania, Denise the AAV vectors given to treat canine is delivered.
Sabatino and colleagues published a paper hemophilia sometimes integrated into the In November 2020, Intellia Therapeutics
in Nature Biotechnology showing potential dogs’ liver cells, creating clonal expansions began a phase 1 trial of the world’s first
liver problems that had emerged in dogs that have the potential to become cancerous. systemically administered CRISPR–Cas9
nearly a decade after they were treated with But these problems take years to develop therapy, for hereditary transthyretin
an AAV gene therapy for canine hemophilia in humans. Problems like these are not amyloidosis with polyneuropathy. Instead of
1314 Nature Medicine | VOL 27 | August 2021 | 1312–1315 | www.nature.com/naturemedicinenews feature packaging the gene-editing system in a viral gene editing is therefore not an option for therapy with interest. He studies a group vector, Intellia is using a lipid nanoparticle, low resource settings. of hereditary lysosomal disorders that are somewhat akin to the method used in “Low-income countries in sub-Saharan fatal in childhood. Colombia has the world’s the mRNA vaccines against SARS-CoV-2 Africa tend to lack the significant highest rates of a mucopolysaccharide developed by Moderna and BioNTech– infrastructure required to broadly provide storage disease known as Morquio A Pfizer. Preclinical research showed that the bone marrow transplants, let alone gene syndrome. Díaz says that although Morquio CRISPR–Cas9 therapy knocked down more therapy, which requires the cells to be A syndrome is the perfect candidate for than 97% of the misfolded transthyretin removed, shipped, genetically modified, gene therapy, getting interest from the protein. The advantage to this method, and returned to the patient,” says Betsy pharmaceutical industry and securing according to Hamilton, is that patients can Foss-Campbell, Director of Policy and funding remains a challenge, because the receive multiple doses over time, since their Advocacy at the American Society of Gene condition is vanishingly rare elsewhere in immune systems will not form antibodies and Cell Therapy. the world. What the field needs, he says, against the vector. In late June 2021, Intellia are more local solutions, developed published the first results of the trial, which Equity of therapy for specific populations affected by showed a dose-dependent drop in serum With an eye toward addressing specific diseases. transthyretin levels. this challenge, the Bill & Melinda “This is not like a regular drug. This is Hamilton is working to create a Gates Foundation partnered with not like an aspirin or a paracetamol that you different type of CRISPR–Cas9 system Novartis in February 2021 to bring a can give to the patient and say, okay, take that delivers the gene-editing system as a single-administration, in vivo gene therapy two pills every few hours. This is a different ribonucleoprotein complex that can enter for sickle-cell disease to Africa, where most treatment,” Díaz says. the targeted cell, edit the genome, and of the people with this condition live. This Far from being hamstrung by recent then degrade. Not only does this transient therapy will need to be delivered directly setbacks and challenges, the gene-therapy dosing strategy prevent the development to the patient, without the need to modify field remains hopeful and optimistic. of antibodies against a viral vector, its cells in the lab, and without the need for There are substantial challenges in terms of short-lived time in the cell also means the lengthy and expensive hospitalization. improving delivery and affordability, as well immune system will not raise antibodies If everything goes to plan, says Susan as monitoring long-term safety, but to the against Cas9, Hamilton says. Stevenson, Executive Director at the scientists, they do not seem insurmountable. Ex vivo CRISPR has its own Novartis Institute for Biomedical Research, “Even with all the disappointment and disadvantages, because it requires the a sickle-cell-disease gene therapy may be pain, it’s just an incredibly exciting time removal of hematopoietic stem cells ready for human trials in a little over 5 years. in this field,” Testa says. ❐ for editing in the lab, which are then “It’s a great model to follow. Take the returned as a stem-cell transplant. Trial treatment where the majority of the patients Carrie Arnold participants must undergo treatment with a are,” she says. Science writer, Richmond, Virginia, USA. myeloablative agent such as busulfan, which From his lab at Pontificia Universidad destroys their own stem cells, requiring Javeriana in Bogotá, Carlos Javier Alméciga Published online: 5 August 2021 weeks of hospitalization. Ex vivo CRISPR Díaz has been following advances in gene https://doi.org/10.1038/s41591-021-01467-7 Nature Medicine | VOL 27 | August 2021 | 1312–1315 | www.nature.com/naturemedicine 1315
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