Amid a new era of medicine, gene therapy is a rapidly evolving field at the precipice of revolutionizing healthcare. This disruptive realm of medicine involves genetically modifying cells by introducing, altering, or suppressing a gene to produce a desired therapeutic effect.
The various types of gene therapy include viral vector-based gene therapy, where a new, exogenous gene is inserted into the body and directly delivered to the required tissue by viral vectors such as adeno-associated virus (AAV) vectors 1. A similar method is non-viral vector-based gene therapy, where synthetic delivery vectors such as lipid- or polymer-based vectors are used for the systemic delivery of DNA 2.
Then, there is cell/gene modification, where genetic modification techniques such as CRISPR-Cas9 are employed to precisely modify and repair a damaged, endogenous gene in the body 3. Another similar therapeutic is antisense oligonucleotide (ASO) therapy, which involves ASOs binding to messenger RNA (mRNA), altering the subsequently produced protein 4. However, ASOs are often not considered a type of gene therapy since they act on RNA rather than DNA and therefore only provide a short-lasting, transient therapeutic effect.
In this article, we will discuss the past, present, and future of vector-based gene therapies.
The concept of gene therapy was first proposed in the 1960-70s 5. Then, the 1980s saw the first successful gene transfer into mammalian cells: scientists at MIT and Harvard Medical School successfully transferred bacterial gene encoding resistance to the neomycin analog G418 into pluripotent hematopoietic stem cells using an infectious retrovirus vector 6. This was quickly followed by FDA approval of the first human gene therapy trial in 1990 that saw the retroviral-mediated transfer of functional adenosine deaminase (ADA) into the T-cells of severe combined immunodeficiency (SCID) patients 5,7. Following the death of a patient during a gene therapy trial 8, research focused on improving the safety and efficacy of gene therapeutics before Glybera became the first approved gene therapy in the Western world in 2012, though it was withdrawn from the market in 2017 9. This was followed by the US approving its first vector-based gene therapies: Luxturna in 2017 and Zolgensma in 2019 10–12. Now, gene therapies are being developed and tested for several diseases, including genetic disorders, cancers, and infectious diseases 13–15.
Gene Therapy: Where Are We Now?
As of 2023, we find ourselves in an exciting era for gene therapy, with several therapeutics having received approval and many more under development. To date, there have been 331 phase I, II, and III clinical trials to assess the safety and efficacy of AAV-based gene therapies, one of the most actively investigated types of gene therapy, for a plethora of human genetic diseases 13.
Of these, the FDA has approved five AAV-based therapies 13: Luxturna, Zolgensma, Hemgenix, Elevidys, and Roctavian. There are currently two FDA-approved Lentivirus (LV)-based gene therapies, Zynteglo and Skysona, and one Herpes simplex virus-based therapy, Vyjuvek. A summary of all current FDA-approved gene therapies is shown in Table 1.
As the only FDA-approved viral vector-based gene therapies, their success may be attributed to several factors, including:
- Easy accessibility of the target tissues
Luxturna is injected directly into the eyeball, while Hemgenix, Roctavian, and Zynteglo are injected directly into the bloodstream; both tissues are directly accessible and amenable to treatment.
- Target cells with a low turnover
When developing non-integrating AAV therapies, it is critical to target cells with low turnover, ensuring the therapy is not lost with cell division. Both Luxturna and Zolgensma target post-mitotic cells 16,17.
- Single Genetic Cause
These treatments target diseases with a single, well-characterized genetic cause, meaning the therapy can effectively replace or supplement the function of the faulty gene.
- Target conditions with significant unmet medical needs
Before the development of these gene therapies, treatment options were limited, and the diseases often led to severe disability or early death. Additionally, targeting rare diseases with previously unmet medical needs has the advantage of an uncrowded drug market with limited competition.
Challenges and Limitations Facing Gene Therapy
Gene therapy holds tremendous promise for treating many diseases, but several challenges remain, including potential immune responses, issues with tissue targeting, and high costs.
- Immune Response
Another significant challenge with gene therapies is the potential for immune responses. In many cases, the low efficacy of AAV therapies means that high doses are needed to produce the desired effect 13. However, host cells cannot distinguish between AAV viruses and AAV vectors, meaning an immune response is provoked, often resulting in adverse effects 13. Immune reactions will vary between patients, rendering it important to develop novel methods of predicting patient immune responses. An immune response means that patients can only receive the therapy once, which presents a problem if the first round is ineffective. Currently, researchers are working on ways to overcome this. One strategy is to use immunosuppressant drugs during therapy.
Another strategy is to use different types of vectors or capsid-modified AAV vectors, which can avoid the immune reaction, improve tissue targeting and improve efficacy 13. Improving transduction efficiency is key for reducing the required dose and evading immune responses 18. The main strategies are directed evolution and rational design/engineering. Directed evolution involves creating a library of capsid variants and selecting those with favorable properties. For example, directed evolution was used to generate AAV2.5T, a variant of AAV2 and AAV5 with improved infectivity 19. Rational design utilizes structural and mechanistic knowledge of AAV capsids to introduce targeted modifications to achieve desired properties. This may include site-directed mutagenesis, sequence insertion, and surface residue alteration. For example, tyrosine residues in the AAV2 capsid were mutated to phenylalanine to reduce phosphorylation and ubiquitination, leading to enhanced transduction efficiency and escape from proteasomal degradation 20.
- Tissue Targeting and Optimal Vector Selection
Efficient, precise vector targeting of an optimally designed vector to the appropriate cells or tissue is critical for reducing the risk of off-target effects, enhancing the efficacy of the treatment, and reducing the required dose, which can bring down production costs and reduce the likelihood of severe immune reactions 21.
Vector pseudotyping is a strategy for improving the efficacy and versatility of viral delivery vehicles 21. It involves replacing the viral envelope proteins – the proteins on the viral surface that interact with the host cells – with those of another virus. Since different viruses have different host ranges, by selecting envelope proteins from a virus that naturally infects the desired cell type, the vector can be targeted to specific cells 22,23. Using envelope proteins from viruses that the host has not yet encountered has also proven a useful strategy for evading immune responses. Currently, engineered AAV capsids are being developed to improve the clinical efficacy of liver-directed gene therapy 24. LV pseudotyping is being used to alter and improve their tropism for different cell types including hematopoietic cells and is currently being investigated for treating various genetic diseases 25.
Additionally, selecting advantageous features can enhance vector stability and transduction efficiency. An important consideration is the integration status of the AAV-delivered gene with the host genome, and how this will affect gene expression and treatment effectiveness over time. For example, following Luxturna therapy, there is no integration of the AAV-delivered gene into the host genome, meaning the exogenous gene will be diluted over time following cell division 26. The rate of this is directly dependent on the turnover rate of the target cells. In the case of Luxturna, the targeted RPE cells have a very low turnover rate, rendering the therapy highly effective for 3 to 7.5 years 26–28. However, in cells with high turnover rates, integrating vectors such as retroviral vectors are favorable 29. Another consideration is the packaging limit of vectors; in most cases, only single, relatively short genes can be packaged into vectors and delivered to cells. The maximum size of the gene that can be delivered depends on the viral vector; the capacity of AAVs is relatively small compared to LVs 26.
The extraordinarily high cost of gene therapies significantly impacts their development, rollout, and ultimate success 30,31. Hemgenix currently takes the lead as the most expensive gene therapy with a single dose costing $3.5 million 31,32. There are several contributory factors to the high costs of gene therapies.
Firstly, gene therapies are expensive to develop and produce compared to more well-characterized small molecule therapeutics. Gene therapies are often single-dose treatments, meaning that the price per dose is high compared to routine medications. However, the lifelong treatment costs of routine medications are significant, and over extended periods may result in a higher overall cost. During development, manufacturers undertake lengthy assessments to determine suitable pricing, including assessing measures of cost-effectiveness: quality-adjusted life year (QALY) and equal value of life years gained (evLYG). These are likely to be much higher for a single-dose therapy that provides a cure for an otherwise debilitating chronic condition, compared to a lower-cost medication that treats only some of the symptoms 33.
However, the cost of gene therapy represents a significant barrier to access 30. Generally, gene therapies are generally not paid for by the individual but instead rely on healthcare systems funded by the state, or health insurance, often subsidized by employers. Reimbursement models vary across countries and depending on the therapy 34.
In European countries, there is usually a centralized healthcare system that undertakes health technology assessments (HTAs) and determines reimbursement models and conditions for novel therapies 34. Generally, many gene therapies are covered by healthcare systems, but only for patients who are determined to be eligible, which varies from country to country and has an impact on uptake across different markets. European regulations on drug costs limit many gene therapies from being made available; two approved (non-AAV-based) products – Skysona for adrenoleukodystrophy and Zynteglo for beta-thalassemia – were withdrawn from the European market due to their extremely high costs and unsuccessful negotiations on reimbursement models 35.
In the United States, the healthcare system is fragmented into several public and private health insurance bodies, all of whom make independent decisions on which gene therapies to cover, and under what conditions 34. Moreover, in countries like the US where drug costs are not regulated, health insurance companies are beginning to restrict coverage of gene therapies 31.
The Future of Gene Therapy: Where Are We Going?
Gene therapy has come a long way since its conception in the 1970s, and though challenges remain, the future of gene therapy is bright. Ongoing research aims at refining treatment strategies to develop more targeted, accessible, and affordable gene therapies.
Novel viral targeting techniques such as vector pseudotyping are likely to enhance targeting and efficacy and have the potential to overcome issues with immune responses 21. The ability to precisely target specific cells within less accessible tissues, such as the brain and lungs, is predicted to pave the way for gene therapies targeting a broad range of diseases 36.
CRISPR-based therapies, which target and directly edit specific DNA sequences, are revolutionizing the field of gene therapy 3. This gene modification technique is more accessible than other methods, which may correspond to lower R&D costs and cheaper therapies, though it is too soon to be sure 31. Exa-cel, a CRISP/Cas9-based gene therapy aimed at treating sickle cell disease and beta-thalassemia, has shown remarkable success in ongoing phase III trials, leading to the FDA granting it priority review status.
Other upcoming gene therapies include AMT-130, the first experimental AAV-based therapy aimed at treating Huntington’s disease, which is showing promising results in ongoing Phase I/II trials 37. Another one to watch is MCO-010, a treatment for retinosa pigmentosa that is currently in Phase IIb trials and has received orphan drug and fast-track designation. Finally, Fidanacogene elaparvovec is a novel gene therapy targeted at Hemophilia B, which utilizes a capsid-engineered AAV vector to deliver functional factor IX.
Commercial Strategy Considerations for Gene Therapies
It is a truly exciting time in the industry of gene therapy as it grows rapidly, fuelled by an increase in approvals and rising investment in R&D. The emergence of the first competitor product: Fidanacogene elaparvovec, which may soon compete with Hemgenix for space in the Hemophilia B gene therapy market, is indicative of a shift from the market’s introductory phase into the growth phase, within which commercial strategy will be crucial to determine key players.
As in any competitive market, pricing and efficacy will play a substantial role in deciding who gains market share. First-to-market advantage means that competitor products will need to either be considerably cheaper or show significantly higher efficacy to be in with a chance of competing. Due to the pre-established regulatory framework and increased awareness, follow-on drugs are usually far cheaper to get to market than first-in-class players, meaning companies may well be able to charge a lower price per dose. Pricing decisions will be pivotal, given the cost sensitivity of the end customers, namely government bodies and insurance companies.
As the industry matures, another factor to be considered is the loss of market exclusivity. The FDA grants enhanced market exclusivity for seven years under Orphan Drug designation, a common status for gene therapy indications, and up to twelve years in total under Reference Product Exclusivity. Then, other manufacturers can produce biosimilar drugs and market them for a fraction of the price. Approved in 2017 with Orphan Drug designation, Luxturna will be the first gene therapy to lose exclusivity in the coming years. This creates a push for existing therapies to change their strategy to remain competitive: either by dropping prices or creating a second-generation therapy with better efficacy.
Moreover, the single-dose nature of many gene therapies means that, for low-incidence diseases such as Hemophilia, once the population of eligible patients is treated, uptake will naturally slow, presenting a further challenge following the loss of exclusivity and increased competition. For higher-incidence diseases such as Huntington’s disease or SMA, revenue is less sensitive to these factors and can be sustained by treating new patients each year. Uptake so far and predicted uptake in terms of sales are summarized in Table 1, according to Evaluate published reports.
Conclusions & Future Perspectives
In conclusion, gene therapy represents a significant shift in the landscape of modern medicine, offering the potential to treat or even cure diseases at their genetic root. However, many challenges remain to be overcome, including high costs, immune responses, and issues with tissue targeting. Strategies like vector pseudotyping and gene-editing tools like CRISPR-Cas9 offer promising solutions, potentially enabling more targeted, efficient treatments.
The successes of the FDA-approved vector-based therapies serve as important indicators of what the future may hold. They highlight the importance of targeting easily accessible tissues with low cell turnover rates. Furthermore, AAV-based systems remain appealing for future therapies, since they are well-researched, have established regulatory frameworks, and do not generally integrate into the host genome, reducing the risk of complications. Due to the proven safety and efficacy of approved AAV-based therapies, novel therapies have begun to be granted fast-track approval status by the FDA, representing a considerably shorter approval timeline (from ~1 year to ~8 months).
While substantial hurdles still need to be overcome, the rapid advancements in this field provide an exciting outlook for the future of gene therapy. The next decade will likely witness an expanding landscape of gene therapy applications, broadening the range of treatable conditions and making these treatments more accessible to patients worldwide. With this, the market is set to grow exponentially and become more competitive than ever before.
Contributors: Eunju Chung, Ph.D., Ryan Franca M.D., Claudio Ingold, Rita Lopez
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