5 important issues facing the field of gene therapy in 2021

Three years ago, the FDA granted a landmark approval for Luxturna to be used to treat a genetic retinal disease (IRD) that can lead to blindness.
is the first truly gene therapy in the U.S. market, marking the official beginning of the era of gene therapy and igniting a fire in the gene therapy market.
since then, the agency has approved another gene therapy for spinal muscular dystrophy (SMA), Zolgensma, and has gave the green light to dozens of biotech and pharmaceutical companies to begin clinical testing of other gene therapies.
, gene therapy for a range of diseases, including haemophilia, sickle cell disease and several types of muscular dystrophy, is now in clinical trials, and new science is inspiring research.
, however, the field of gene therapy faces major problems in 2021 after a series of regulatory and clinical setbacks overshadowed optimism.
, drugmakers and investors will face five major problems this year, according to a recent article by BioPharma Dive, a foreign biopharmaceutical website.
01's latest setback a warning sign for gene therapy? Last year, industry insiders widely expected the FDA to approve a high-profile gene therapy, Roctavian, to treat haemophilia A, a more common blood disease.
, however, unexpectedly refused to approve Roctavian in August and asked its developer, BioMarin, to collect more data.
, Audentes Therapeutics reported the third clinical trial in which participants died after receiving gene therapy for a rare neuromuscular disease.
tragedy is reminiscent of past safety scares about gene therapy, even though gene therapy, which is currently in human clinical trials, generally appears to be safe.
less than five months, the field of gene therapy has suffered two more setbacks.
UniQure is exploring whether liver cancer in a study volunteer was caused by its gene therapy for haemophilia B.
, one of the industry's top developers, is also facing serious questions about its gene therapy for Duchy muscular dystrophy (DMD) after it was revealed that a key study had failed to meet one of its main objectives.
in each case, the drugmakers involved gave optimistic explanations and reasons.
BioMarin still wants regulatory approval; Audentes' clinical trials are now FDA-approved to resume testing; UniQure believes cancer cases are unlikely to be related to treatment; and Sarepta believes its negative data is the reason for the study's design.
, but in summary, these developments are a powerful reminder that gene therapy still faces risks and uncertainties.
four incidents also highlight lingering concerns about one-off gene therapy.
, for example, when refusing to approve Roctavian, the FDA is concerned that the huge therapeutic benefits that haemophilia patients initially receive may diminish over time.
same time, the deaths in the Audentes study again warned of ultra-high doses of gene therapy.
researchers have long been looking for evidence that replacing or altering genes can lead to cancer, especially in a gene therapy study in the early 2000s, in which four babies developed leukemia.
and Sarepta's negative results were surprising because early signs of significant biological benefits did not appear to translate into significant functional improvements in all patients.
experts still believe gene therapy can deliver its potential.
recent events suggest that it may take longer than some expected to get to this point.
02 FDA raise the standard? Gene therapy is a complex treatment with strict manufacturing standards.
, for example, most of the approximately 60,000 pages of Spark's application for Luxturna approval relate to what the industry calls "chemical, manufacturing and control (CMC)."
, gene therapy is based on many rare single-gene diseases targeted by developers.
if a mutation in a gene causes disease, replacing or otherly processing the gene should be of great benefit.
January 2020, the FDA released eight industry guidance documents on gene therapy, including the CMC, indicating that the agency is closely monitoring the gene (and cell) therapy industry.
Sarepta, Voyager Therapeutics, Iovance Biotherapeutics and Bluebird Bio were forced to revise the development schedule for their gene therapy projects after being asked to provide new details about the production process.
the FDA said standards must be raised.
, FDA officials say the large number of requests for data is the result of a dramatic increase in the number of companies that have passed clinical tests.
03 Gene Editing Unit Overheat? Geulah Livshits, an analyst at Chardan, points out that while there have been setbacks in seeking alternative gene therapies, 2020 has been a "transformative year" for gene-editing therapies.
CRISPR gene editing has been widely regarded as a scientific breakthrough, with two early pioneers, Jennifer Doudna and Emmanuele Charpentier, winning the Nobel Prize in Chemistry.
the year also brought important advances for early adopters of biotechnology.
, editas Medicine and Intellya Therapeutics pioneered the use of CRISPR editing techniques in the human body.
Vertex, a researcher and co-creator of CRISPR Therapeutics, showed that gene therapy using CRISPR-edited stem cells worked well in the top 10 patients treated with sickle cell disease or β thalassemia in two early studies.
are the most concrete evidence yet that CRISPR's clinical applications are delivering on its laboratory commitments.
the companies' treatments are still in their early stages, their progress has sparked enthusiasm among investors.
market capitalisations of CRISPR Therapeutics, Editas and Intellya are close to $25 billion.
Beam Therapeutics, a start-up that uses more precise gene editing methods, is worth nearly $6 billion.
, chief executive of Beam, said: "Gene therapy is bound to play an important role.
I do think that over the past year or so, people have become more aware that if possible, you might rather edit genes than add extra ones.
" clinical trials will prove this, but until then, the sharp rise in gene editing companies' share prices may not be sustainable as valuations rise.
For example, some of the recent growth appears to have been driven by money flowing through exchange-traded funds by all-fronted investors, rather than from investors with investment experience in preclinical or early-stage companies.
, chief executive of Loncar Investments, an investment group in biopharmaceuticals, predicts: "Genetic editing stocks are long overdue for some rationalisation.
companies have targeted similar diseases, most commonly sickle cells and β of thalassemia.
" 04 wave of start-ups be able to develop better tools? Scientists are tasked with replacing defective genes with functional genes, and most have turned to two types of viruses to safely transfer gene instructions to cells.
-related viruses (AAVs) are commonly used in infusion therapy, while researchers studying cells extracted from patients typically choose lyrovirus.
each virus has advantages, but there are obvious disadvantages.
, for example, AAV triggers pre-existing immune defenses in certain people, making them ineligible or unfit for gene therapy.
, slow viruses can directly integrate DNA into the genomes of their infected cells, which is useful in some ways but limited in others.
decades of gene therapy research, scientists have found ways to adapt and modify these viral vectors to better meet their needs, but the basic tools are the same.
Wilson, a pioneer in gene therapy who led the gene therapy study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at an STAT conference last fall that he was "somewhat disappointed" by the slow pace of research into viral vectors.
with more and more gene therapy into clinical trials, the limitations of viral vectors are becoming more and more obvious.
, however, the pace of research may be accelerating.
recently, a number of companies aiming to build better delivery tools have emerged, including Harvard-based start-ups Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222m in an initial public offering.
companies are also interested.
such as Roche, Sarepta and Novart have all worked with Dyno.
at the same time, researchers are developing new ways to cut DNA in gene editing, and Team and other companies are working together to advance different editing methods.
05's bets on big drugmakers work? In the past few years, pharmaceutical companies have invested billions of dollars in gene therapy programs, and few large multinational pharmaceutical companies have been absent from the field.
2020 is no exception, with Bayer and Lilly signing large-scale acquisitions and Pfizer, Novarma, Johnson and Johnson, Yan Jian and Yossbeh also investing on a number of smaller scale.
, which is known for its plasma products, paid $450 million in advance to buy a phase 3 clinical type B hemophilia gene therapy from UniQure, etranacogene dezaparvovec.
at least $30 billion over the past three years on biotechnology deals in gene or cell therapy.
four of these deals accounted for the majority.
all of these deals, while following promising and compelling science, end up betting that one-off gene therapy can be expanded and commercialized as a profitable business.
many of the acquired companies are working to treat very rare diseases that affect hundreds or thousands of people.
, however, a few companies are targeting more widespread diseases, from haemophilia, which is still relatively rare, to diseases such as Parkinson's, which affect millions of people.
Brad Loncar points out that gene therapy must jump out of these extremely rare diseases in order to meet our high expectations, not only for investors but also for society.
commercially, sales of several treatments already on the market in the U.S. have been mixed.
Luxturna is a nichure product that is now owned by Roche.
Zolgensma has a wider range of applications, winning about $1 billion in profits for Novarma in the year and a half since its launch.
, two cell therapies from Novaral and Gilead are also struggling to be commercially successful.
largest commercial test in the field of gene therapy is expected this year, bioMarin's Type A haemophilia gene therapy Roctavian is expected to receive regulatory approval to go on sale.
the FDA could mean a one-year delay in the drug's U.S. launch.
, the challenges of pricing, reimbursement and patient access for gene therapy remain significant after the market launch.
source: 5 questions facing gene therapy in 2021