gene therapy revolutionizing hemophilia treatment, unlocking new research opportunities
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in the case of hemophilia, the new genes give the body instructions on how to make the specific protein for clotting blood.
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dr. david lillicrap, leading canadian hematologist and researcher is feeling pretty good these days. after more than three decades of study with colleagues in canada and around the globe, gene therapy for the bleeding disorder hemophilia is closer to transforming care for patients than ever before.
health canada recently approved two single-dose gene therapies sold under the brand names hemgenix and beqvez, which are game-changers for patients and doctors. these one-time injections are for hemophilia b, the less common but more serious form of hemophilia. hemophilia b affects about 700 canadians.
a similar one-time therapy for hemophilia a has conditional approval by the u.s. food and drug administration.
“i always believed that this would eventually get to the clinic,” dr. lillicrap says from his lab at queen’s university in kingston, ont. “even seeing a few patients in the country who take this and it removes the hemophilia and all the worries associated with that, that would be a fantastic outcome.”
understanding hemophilia: from traditional care to genetic solutions
hemophilia is a rare inherited disease where blood doesn’t clot normally, so patients bleed spontaneously, excessively or for a longer time than is typical. it’s caused by a mutation in one of the genes responsible for the proteins that are needed for clotting the blood. those with severe hemophilia can bleed spontaneously into their muscles or joints causing chronic joint disease and pain. they can also bleed into their brain, which is more rare, but this bleeding can cause seizures, paralysis or can potentially be fatal, according to the u.s. centers for disease control and prevention.
the current standard of care is recurring intravenous infusions of the clotting protein to help control and prevent bleeding episodes.
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“the results we’ve seen from the late-stage clinical studies have been very, very encouraging,” dr. lillicrap says. “the breakthrough study for hemophilia gene therapy started in 2011 with about 10 patients. those patients are now 12 or 13 years post single-injection and they’re still doing very well. this is a one-time treatment and while everyone’s very cautious about using the word ‘cure,’ this is long-term. honestly, it may be a cure.”
while he and many experts in genetics have worked long and hard for this to happen, dr. lillicrap is quick to point out that there have been other molecular innovations in hemophilia therapy that have made treatments much more effective than they were 20 years ago.
these therapies have also taken a similar timeframe to mature, making tremendous strides in the last five to 10 years, he says. “we are beginning to see the fruits of molecular biology at a time when the patients are now able to choose several different, very effective and very safe treatments.”
in fact, gene therapy research is ushering in a new era of personalized medicine. it has made it possible to analyze an individual’s genetic profile – the unique sequences and variations in their dna – to tailor treatments for better outcomes.
the future of gene therapy: expanding horizons in medicine
hemophilia has long been a focus for gene therapy for a few reasons. it’s considered an ideal model to work from because collecting the study material requires only a needle to get a blood sample, for the most part. it’s also a condition caused by a single gene problem, unlike cardiovascular disease which involves the heart, brain and circulatory system with multiple genetic components. for hemophilia, even a modest increase in the person’s ability to clot bleeding can have a significant benefit.
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dr. lillicrap explains that the clotting, or coagulation, genes in hemophilia were among the first genes to be characterized and cloned back in the early 1980s, before the global human genome project was launched to identify and map out the sequence of about 20,000 human genes that it takes to make a person (some experts say there could be thousands more still to be determined).
so, the basic building block for gene therapy and hemophilia was present early on.
canada is a leader in this specialty with a network of more than 20 hemophilia treatment centres across the country that have a vested interest in bringing hemophilia gene therapy into practice. some centres have patients who have been treated in the gene therapy pre-approval clinical trials. dr. lillicrap’s team runs one of two large dog colonies in the world where there are now 30 dogs undergoing gene therapy for studying hemophilia.
“canada hits pretty heavily in terms of molecular science,” he notes, adding that other molecular groups are also leading in gene therapy for cancer and other inherited diseases.
so how does gene therapy work?
basically, new working genes are introduced into a person’s cells to fight disease. in the case of hemophilia, the new genes give the body instructions on how to make the specific protein for clotting blood. right now, there are several different kinds of gene therapy in research, including gene transfer, gene editing and cell therapy.
the win for hemophilia patients is through gene transfer, where new working genes are packaged into a “vector” and transferred into liver cells in the body so they can start producing the clotting protein. vectors are actually a type of virus that has been changed to remove the material that brings on illness and infection. consider covid-19, for example. viruses are smart, aggressive, and do a very good job of getting inside human cells.
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“viruses have evolved over millions of years to be very, very effective at getting their genomes into cells,” says dr. lillicrap. “gene therapists steal things from nature, so this is a good example where the delivery system is stolen from viruses. we all know from the pandemic how good viruses are at making people ill. well, now we’re stealing bits from them to deliver something that’s making people much better.”
navigating challenges and opportunities in gene therapy
however, there are still hurdles for hemophilia patients and their specialists when it comes to new treatments, he adds. once health canada approves a new drug, it goes through a further assessment by the canadian agency for drugs and technologies in health which can take another one to two years. “so that’s the sticking point, as you can imagine, because the cost of these one-time treatments for hemophilia is somewhere between $2.5 and $3 million.” after that process, provinces and territories do their own economic evaluations to determine drug plan coverage for those most in need.
advocacy for a better pharmaceutical system hasn’t gone unheard, and in december the federal government announced funding dollars and the creation of the canadian drug agency to work with provinces and territories to improve the end-to-end process. the agency will also work to increase pan-canadian data collection and expand access to drug and treatment data to better inform health decisions.
another key group in the gene therapy space is the non-profit centre for commercialization of regenerative medicine founded to bridge the gap between academia and industry to bring investors and manufacturing contracts for specialty therapies to canada. the goal is to have an infrastructure that supports the medical technology sector like silicon valley.
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for now though, when trainees go through dr. lillicrap’s research program and complete their phds, almost all head south of the border to the boston area or to california if they want to work in the commercial and industrial aspects of gene therapy or diseases.
“we have a minimal amount of activity and opportunity here, but there is so much activity in the states. so that’s where we are losing high quality trainees who would love to stay in canada,” he says.
one of the strategies for promoting business development is the big-picture goal of using the science learned from tackling rare diseases like hemophilia and applying it to mainstream health problems that affect large numbers of people.
cancer is a key one, with one in four canadians expected to die from the disease. car t-cell therapies have entered the mainstream of cancer treatment, which is a way of genetically altering a patient’s own immune cells to fight cancer.
gene editing is also showing incredible promise with the 2020 nobel prize work on crispr/cas9 genetic scissors to change the dna of animals, plants and microorganisms. the first crispr medical treatment was approved in the u.s. in december to edit a gene involved in red blood cell shape and function for sickle cell disease, another rare blood disorder.
gene therapy is no longer in our distant future. it’s here, sparking hope and excitement in the space.
“the big diseases that we need to understand and treat are cardio respiratory diseases and neurological diseases. i mean, gene therapy for alzheimer’s. how wonderful would that be? and then malignant disease, cancer. those are the three big areas. hemophilia is a rare disease. it’s a relatively simple rare disease. all of those other diseases are very common and unfortunately also very complicated,” says dr. lillicrap. “molecular advances will definitely impact all of those.”
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