Gene therapy is hard to do, hard to reverse, prone to error, and immunogenic. Most traits are virtually omni-genetic, meaning that you have to change lots of genes to get the desired effect. It is often hard to even identify the relevant genes or causality, much less target and change them. There have been many expensive clinical trial failures here.
Contrast with the wonders of small molecule drugs, which avoid many of these issues. Worse, consider all the modalities that might substitute for gene therapies: RNAi, RNA-targeted drugs, vaccines, antibodies, CAR-T, in-vivo CAR-T, stem cell therapies, and 3D printed organs. Each has an advantage over gene therapies in some aspect, and many are likely to be cheaper.
That said, monogenic disorders like Sickle cell, Tay-Sachs, Hemophilia, Duchenne Muscular Dystrophy, and Huntington’s are good directions for human gene therapy.
(Of course, genetic modification in plants and animals dodges many of my concerns and seems promising)
This is broadly in my field, and I think about this a lot. It’s a common argument. Tl;dr: all drugs have problems, all trials are expensive, finding patients is often the trial bottleneck, and gene therapies are just a tool in the tool box, sometimes perfect, other times not.
Overall, this critique reads as a list of disadvantages of gene therapies and advantages of alternatives, which is useful but not necessarily reason to be uniquely skeptical of gene therapies. All treatment modalities have advantages and disadvantages. You’re neither providing systematic criteria for thinking about whether the tool-indication pairing is a good fit, nor for any claim that there’s excessive resources being put into gene therapies in general, nor for there being an overestimate on their potential. The work this does is inject some bad vibes into the topic of gene therapy that think is unhelpful.
Gene therapy is hard to do, hard to reverse, prone to error, and immunogenic.
Gene therapies are the most platform-compatible technologies we have in biomedicine. Advancements in testing, prediction of off-target effects, production, delivery, integration, immunosuppression, and monitoring expand capabilities across broad classes of gene therapies. With gene therapies, we have more capacity to engineer biomedical solutions than in any other therapeutic class, with the possible exception of mechanical devices.
Gene therapies are generally off-the-shelf IV infusions. The difficulty with viral vectors, like AAVs, is the immune response, as you note. This requires temporary intensive care in a specialized facility, which are being aggressively expanded. As non-immunogenic delivery mechanisms improve, the requirement for that level of specialized care will diminish.
The one-and-done nature of gene therapies has also required innovation in funding, since a single insurer doesn’t want to be on the hook for paying the full upfront costs of a lifetime cure when the reduced medical costs play out over a lifetime. Fortunately, that work’s largely been done in the United States through the CGT access model.
It’s true that a toxic gene therapy can be deadly, typically through insertional mutagenesis leading to cancer. But that’s a side effect, and many drugs have toxic or deadly side effects. It’s a downside we can quantify and control. Solutions then propagate to all gene therapies, which is not always case for molecular engineering of small molecules and peptides.
Side node: ex vivo cell therapies (where cells are genetically modified outside the body, then infused into the patient) and gene therapies (where genetic material is delivered to the patient’s cells in vivo) are often lumped together. I’m specifically talking about gene therapies. Cell therapies are also useful, but are much more challenging to manufacture.
Most traits are virtually omni-genetic, meaning that you have to change lots of genes to get the desired effect. It is often hard to even identify the relevant genes or causality, much less target and change them. There have been many expensive clinical trial failures here.
A way of reframing this is to ask about the marginal contribution to human disease burden attributable to N-gene disorders. What fraction of disease burden is monogenic, bi-genic, etc? A recent article suggests about 0.36% of the disease burden might be attributable to monogenic disorders.
Rare genetic diseases affect numerous children and young adults. While the number of individuals or families affected by any unique genetic disease might be small, the total number of all individuals affected by all rare genetic diseases is substantial. The incidence and prevalence of genetic diseases in children are challenging to estimate. In 1977, monogenic diseases were estimated to collectively affect about 10 individuals per 1000 live births, including 7/1000 for autosomal-dominant, 2.5/1000 for autosomal-recessive, and 0.4/1000 for X-linked inherited diseases [1]. In 1988, Baird et al. studied more than one million consecutive live births from a Canadian population-based registry. They reported that genetic diseases were expected to occur in ≥53/1000 live-born individuals younger than 25 years of age [2]. The most frequent (46.4/1000) genetic diseases were accounted for by multi-factorial diseases present at birth or before age 25 years. Single-gene disorders, present in 3.6/1000, included autosomal-dominant (1.4/1000), autosomal-recessive (1.7/1000), and X-linked recessive disorders (0.5/1000), followed by chromosomal anomalies in 1.8/1000, and genetic diseases with unknown etiology in 1.2/1000 [2]. These authors excluded all congenital anomalies that used to be included in estimates of genetic diseases before their study [2].
Another study suggests that about 10% of infant mortality at Boston Children’s Hospital was attributable to monogenic disorders.
All clinical trials are expensive. You’d need to provide evidence that gene therapy trials are more expensive or have a higher failure rate. But even then, the cost in dollars isn’t the most important. Often, the bottleneck for trials isn’t money, but patients. Gene therapy trials enable treating previously untreatable patients. Where patients were going to die or live with a debilitating disorder, and where the upside is a cure, the risk of failure is acceptable. We can try more than once. We’re in the early stages of figuring out gene therapies, and as we grow in capability, we’ll see the failure rate and costs declinein tandem for a given level of disease complexity.
Contrast with the wonders of small molecule drugs, which avoid many of these issues. Worse, consider all the modalities that might substitute for gene therapies: RNAi, RNA-targeted drugs, vaccines, antibodies, CAR-T, in-vivo CAR-T, stem cell therapies, and 3D printed organs. Each has an advantage over gene therapies in some aspect, and many are likely to be cheaper.
Let’s break this down.
Biologics infusions, including enzyme replacement, RNA or RNAi therapy, are proven technologies for specific classes of disease. However, the body is homeostatic. If you suppress toxic RNA via RNAi, then various feedback loops may simply compensate with more production of the toxic gene. RNAi is also messy. A toxic gene driven by a single SNP may be extremely hard to suppress without simultaneously suppressing the healthy copy. There’s also a convenience issue. Infusions require lifelong periodic treatment, whereas gene therapies can be one-and-done.
There’s less in the way of disease-specific scientific uncertainty with a gene therapy. By the time you’re thinking about RNA or proteins, there are many more layers of complex regulation involved. Vaccines and antibodies introduce a massive new level of complexity and heterogeneity, because you’re trying to use the messy, risky mechanisms of the patient’s immune system to implement therapy. If being immunogenic is a downside you’re worried about, this has that same downside, but moreso, because it requires sustained, lifelong immune activation or immunosuppression, compared to the temporary immunosuppression applied during the gene therapy.
Ex vivo cell therapies (CAR-T, stem cells, 3D printed organs) are vastly more complex and expensive than gene therapies. Look into the Casgevy rollout (cell therapy for sickle cell) for an example. For now, autologous cell therapies sidestep the immunogenicity issues of gene therapies, which is an important advantage. Allogeneic cell therapies are off-the-shelf, but are immunogenic or currently in trials and not yet shown to work. There are broad classes of genetic disorders cell therapies can’t treat. Human organ transplants are scarce. Humanized animal organ transplants are promising but unproven, and there are many diseases much more straightforward to target via a gene therapy. Would you rather get a one-time IV infusion to treat Danon disease, or a transplanted humanized animal heart?
This is broadly in my field, and I think about this a lot. It’s a common argument. Tl;dr: all drugs have problems, all trials are expensive, finding patients is often the trial bottleneck, and gene therapies are just a tool in the tool box, sometimes perfect, other times not.
Overall, this critique reads as a list of disadvantages of gene therapies and advantages of alternatives, which is useful but not necessarily reason to be uniquely skeptical of gene therapies. All treatment modalities have advantages and disadvantages. You’re neither providing systematic criteria for thinking about whether the tool-indication pairing is a good fit, nor for any claim that there’s excessive resources being put into gene therapies in general, nor for there being an overestimate on their potential. The work this does is inject some bad vibes into the topic of gene therapy that think is unhelpful.
Gene therapy is hard to do, hard to reverse, prone to error, and immunogenic.
Gene therapies are the most platform-compatible technologies we have in biomedicine. Advancements in testing, prediction of off-target effects, production, delivery, integration, immunosuppression, and monitoring expand capabilities across broad classes of gene therapies. With gene therapies, we have more capacity to engineer biomedical solutions than in any other therapeutic class, with the possible exception of mechanical devices.
Gene therapies are generally off-the-shelf IV infusions. The difficulty with viral vectors, like AAVs, is the immune response, as you note. This requires temporary intensive care in a specialized facility, which are being aggressively expanded. As non-immunogenic delivery mechanisms improve, the requirement for that level of specialized care will diminish.
The one-and-done nature of gene therapies has also required innovation in funding, since a single insurer doesn’t want to be on the hook for paying the full upfront costs of a lifetime cure when the reduced medical costs play out over a lifetime. Fortunately, that work’s largely been done in the United States through the CGT access model.
It’s true that a toxic gene therapy can be deadly, typically through insertional mutagenesis leading to cancer. But that’s a side effect, and many drugs have toxic or deadly side effects. It’s a downside we can quantify and control. Solutions then propagate to all gene therapies, which is not always case for molecular engineering of small molecules and peptides.
Side node: ex vivo cell therapies (where cells are genetically modified outside the body, then infused into the patient) and gene therapies (where genetic material is delivered to the patient’s cells in vivo) are often lumped together. I’m specifically talking about gene therapies. Cell therapies are also useful, but are much more challenging to manufacture.
Most traits are virtually omni-genetic, meaning that you have to change lots of genes to get the desired effect. It is often hard to even identify the relevant genes or causality, much less target and change them. There have been many expensive clinical trial failures here.
A way of reframing this is to ask about the marginal contribution to human disease burden attributable to N-gene disorders. What fraction of disease burden is monogenic, bi-genic, etc? A recent article suggests about 0.36% of the disease burden might be attributable to monogenic disorders.
Another study suggests that about 10% of infant mortality at Boston Children’s Hospital was attributable to monogenic disorders.
All clinical trials are expensive. You’d need to provide evidence that gene therapy trials are more expensive or have a higher failure rate. But even then, the cost in dollars isn’t the most important. Often, the bottleneck for trials isn’t money, but patients. Gene therapy trials enable treating previously untreatable patients. Where patients were going to die or live with a debilitating disorder, and where the upside is a cure, the risk of failure is acceptable. We can try more than once. We’re in the early stages of figuring out gene therapies, and as we grow in capability, we’ll see the failure rate and costs declinein tandem for a given level of disease complexity.
Contrast with the wonders of small molecule drugs, which avoid many of these issues. Worse, consider all the modalities that might substitute for gene therapies: RNAi, RNA-targeted drugs, vaccines, antibodies, CAR-T, in-vivo CAR-T, stem cell therapies, and 3D printed organs. Each has an advantage over gene therapies in some aspect, and many are likely to be cheaper.
Let’s break this down.
Biologics infusions, including enzyme replacement, RNA or RNAi therapy, are proven technologies for specific classes of disease. However, the body is homeostatic. If you suppress toxic RNA via RNAi, then various feedback loops may simply compensate with more production of the toxic gene. RNAi is also messy. A toxic gene driven by a single SNP may be extremely hard to suppress without simultaneously suppressing the healthy copy. There’s also a convenience issue. Infusions require lifelong periodic treatment, whereas gene therapies can be one-and-done.
There’s less in the way of disease-specific scientific uncertainty with a gene therapy. By the time you’re thinking about RNA or proteins, there are many more layers of complex regulation involved. Vaccines and antibodies introduce a massive new level of complexity and heterogeneity, because you’re trying to use the messy, risky mechanisms of the patient’s immune system to implement therapy. If being immunogenic is a downside you’re worried about, this has that same downside, but moreso, because it requires sustained, lifelong immune activation or immunosuppression, compared to the temporary immunosuppression applied during the gene therapy.
Ex vivo cell therapies (CAR-T, stem cells, 3D printed organs) are vastly more complex and expensive than gene therapies. Look into the Casgevy rollout (cell therapy for sickle cell) for an example. For now, autologous cell therapies sidestep the immunogenicity issues of gene therapies, which is an important advantage. Allogeneic cell therapies are off-the-shelf, but are immunogenic or currently in trials and not yet shown to work. There are broad classes of genetic disorders cell therapies can’t treat. Human organ transplants are scarce. Humanized animal organ transplants are promising but unproven, and there are many diseases much more straightforward to target via a gene therapy. Would you rather get a one-time IV infusion to treat Danon disease, or a transplanted humanized animal heart?
This is a really excellent response thank you.