20 Years of Gene Therapy: From Concept to Clinic

5th October 2022 - Last modified 19th October 2023

20 years of Alto. 20 years of science. #11

By Pete Cussell PhD, Science Writer

As part of Alto Marketing’s 20 year celebrations, we’re looking back at some of the most important advances in science over this time in our blog series “20 years of Alto. 20 years of science.” Here, Pete Cussell PhD focuses on gene therapy and the progress made in this field over the last 20 years – from concept to clinic.

When celebrating the major scientific breakthroughs of the last two decades, I thought it would be ill-judged to overlook the topic of gene therapy – an innovation set to transform the world of medicine in an incredibly profound manner. Although gene therapy remains a divisive concept for some, it has already become a success, with an ever-growing list of approved clinical applications.

While gene therapy is not new, over the last two decades, we have witnessed unprecedented progress in the field. Thanks in part to the development of genome editing tools, such as CRISPR-Cas9, plus rapid next generation sequencing (NGS) techniques, the past 20 years have provided the key technological breakthroughs necessary to transform gene therapy from a theoretical possibility to a clinical reality.

Now that gene therapy treatments are increasingly emerging into the clinic, a couple of broad questions remain: What does the future of gene therapy look like? And where do we draw the line in terms of its application?

In this blog, we will explore these questions, and cast an eye upon some of the successful gene therapy treatments helping patients today.

What is gene therapy?

In a nutshell, gene therapy is the transfer of genetic material into a patient to achieve a therapeutic effect. This generally involves rectifying an underlying inherited genetic fault through gene replacement/silencing, or via engineering a patient’s cells to combat a hereditary or acquired disease.

One of the most exciting prospects for gene therapy in the clinic is its ability to provide treatment for conditions that are beyond the reach of traditional medical and pharmaceutical means. The scope of clinically approved gene therapy treatments stands testament to this, providing treatment for rare and often severe diseases. But how is this achieved? There are two main strategies:

In vivo

In vivo gene therapy involves gene transfer directly into a living patient, and is ideally suited for monogenetic disorders, in which a mutation in a single gene gives rise to an inherited condition, such as in cystic fibrosis. This requires the transfer of genetic material into a patient’s cells to either silence or replace the faulty gene, with the aim of restoring normal function [1].

• Achieved by injecting the therapeutic gene, enveloped within a delivery vector, either intravenously or locally to a specific organ

• Vectors are usually non-integrating (introduced into long-lifespan cells to ensure long-term expression)

• Once at the target site, the vector delivers the transgene, where gene silencing or genome editing tools such as RNA interference or CRISPR-Cas9 can be harnessed to silence or replace faulty genes

• Genetic sequencing is often required before treatment to identify each patient’s unique genetic profile and causative gene(s)

• Comes with significant delivery challenges

For a more in-depth overview of genome editing tools, check out our blog on CRISPR-Cas9

Ex vivo

Ex vivo gene therapy is the removal of specific target cells from a patient, which then undergo specific modification with genome editing, before being transplanted back into the patient. This type of gene therapy has been successfully harnessed to tackle both hereditary diseases, such as sickle cell disease, as well as acquired diseases like cancer [2].

• Various cell types have been utilised, including haematopoietic stem cells (HSCs), neural stem cells (NSCs) and T-cells

• Vectors are usually integrating (introduced into a stem cell so that the healthy gene is passed to daughter cells)

• More complex workflow, requiring more steps

• Well-suited to targeting a specific organ rather than for treating a whole organism

• Fewer challenges with delivery

Which treatments are clinically available today?

Clinical gene therapy treatments have been developed for a broad range of disorders, including HIV, cancer, Duchene muscular dystrophy, spinal muscular atrophy, diabetes, sickle cell disease, β-thalassemia, tyrosinemia and cystic fibrosis, among others [3]. Set out below are some of the highlights:

Immunodeficiencies and blood disorders

Some of the biggest success stories have come from the ex vivo modification of HSCs. These self-renewing cells give rise to all blood cell types, and have proven especially effective in targeting blood disorders such as primary immune deficiencies, haemoglobinopathies and metabolic disorders.

The transplanted healthy HSCs can serve as an ongoing source of blood cells of all types. As such, a single treatment can eliminate a host of blood disorders with life-long effect. The genetic modification of a patient’s own HSCs is seen by some as a favourable alternative to stem cell transplantation from a healthy donor as the need to find a closely related donor is negated [4].

Cancer

Another ex vivo treatment, CAR-T cell therapy, has become a highly promising therapy for cancer. Instead of delivering a healthy copy of a specific defective gene, a patient’s T-cells are transfected with a gene that encodes a chimeric antigen receptor (CAR). After transplantation back into the patients, the CAR-T cells can recognise cancer-specific antigens and produce durable effects in the treatment of cancers including B-cell malignancies, leukaemia and lymphoma [5].

For a more detailed look at CAR-T therapy, why not check out our recent blog here

Inherited retinal diseases (IRDs)

IRDs are a group of genetically variable eye disorders, with over 260 causative mutations identified. Individuals with IRD often develop significant visual impairment that can often manifest in childhood, and traditional treatment routes offer little benefit. Recently however, we have seen successful in vivo gene therapies for IRDs make it into the clinic.

In vivo gene supplementation therapy, in which a mutant disease-causing gene is swapped for a healthy copy, has proven to be a powerful tool against IRDs. A local injection is required, resulting in slowed disease progression and restored visual function. IRD gene therapy success has been boosted with the development of NGS panels to determine which of the 260+ mutations are exhibited by each patient, allowing for highly personalised treatment [6].

What are the dangers associated with gene therapy?

Since its conception, various concerns have been raised about the safety of gene therapy, and during the early days of therapy trials, several led to unexpected side-effects and in some cases patient deaths [7]. Thankfully, with the rapid progress we have seen over the last 20 years, the majority of these concerns have been resolved.

In terms of safety, the ex vivo therapy approach may have benefits over in vivo, especially regarding off-target gene editing. In vivo approaches must take into consideration any unintended off-target editing, which can manifest in unintended delivery to an off-target cell type, or in the form of unintended editing of an off-target section of the genome. Ex vivo gene therapy avoids this problem by editing the precise cell type, while also allowing an opportunity to screen for successful editing.

In any case, the benefit-to-risk ratio for each individual should be assessed before undergoing gene therapy. Where alternative treatments are available, these should be considered first.

What are the ethical considerations moving forward?

Many of the debates that remain around gene therapy centre around ethics. One of the primary ethical concerns, surrounds the posited idea of germline gene therapy. Up to now, research and clinical applications have largely focused upon targeting body (somatic) cells, but in theory, gene therapy could be conducted within egg and sperm (germ) cells. Doing so would allow the genetic alterations to be passed to future generations.

The idea of germline gene therapy is controversial. While it could protect unborn foetuses from hereditary disease or disorder, it could affect their development or cause side effects that are unknown. Furthermore, the unborn child cannot consent to this treatment. The idea of germline gene therapy also brings into reality the idea of “designer babies” – so where do we draw the line? Some of the main ethical considerations are:

• How can “right” and “wrong” applications of gene therapy technologies be distinguished?

• Who decides which traits are normal and which constitute a disability or disorder?

• Should we be allowed to use gene therapy to enhance physical traits such as height or intelligence?

• Will the high cost of gene therapy render it available only to the wealthy?

The scientific community strives to answer these questions, and a global consensus should be reached before germline therapy is implemented in the clinic.

What are the current obstacles preventing wider applications?

Although there are now dozens of clinically approved treatments, the scope of gene therapy could reach much further given the rapid technological advancements seen in recent years.

Nevertheless, it is the delivery of the therapeutic gene to the target site that remains the biggest challenge.

Viral vectors are overwhelmingly popular as a delivery system, but these can trigger an unwanted immune response in some patients. Furthermore, the manufacturing process for viral vectors is extremely time-consuming and costly, and once manufactured, maintaining their long-term stability and efficacy is problematic. All of these issues limit the scalability of viral vectors and gene therapy itself.

To overcome this, researchers are developing alternative delivery systems that could overcome the safety and production issues posed by viral vectors. Some of the alternative delivery systems in development include nanoparticles, lipids and physical delivery methods [8].

Future prospects

Despite being in its relative infancy in the clinic, gene therapy has achieved huge success, providing treatment for diseases otherwise untreatable by regular therapies. But as of yet, most gene therapies seek to correct monogenetic conditions. Advancements in genome editing could usher in treatments for more complex hereditary disorders with multiple causative genes, unlocking the true potential of gene therapy. We may also see a shift towards more common diseases being targeted, rather than rare diseases.

Most treatments today target easily accessible body regions, such as the eye, however, with improved delivery systems, gene therapy may become available for more difficult-to-target body regions. The nervous system is an obvious example – delivering therapeutics that can pass the blood-brain barrier has long been a conundrum for pharmacologists. Non-viral delivery systems may provide the answer and could revolutionise the treatment of neurological disorders in the future.

Another issue to overcome is the cost associated with gene therapy. With treatments coming in at an extortionate price, this is surely a limiting factor to its wide implementation. As technologies advance further, the cost of treatment will hopefully begin to fall, but future treatments should be designed with end-user cost in mind. 

An exciting future ahead

Gene therapy is one of the most exciting areas of biotechnology today, with ever-accelerating progress and vast possibilities to come. Gene therapy technologies have unlocked unprecedented levels of control over gene delivery, modulation of the immune system, and precise manipulation of the human genome – technologies not imaginable 20 years ago!

Although many opportunities exist, we should all proceed with care and caution. The last 20 years have seen technological advancements significantly outpacing safety testing and trials, which of course should be conducted with the utmost attention to detail. For gene therapy to thrive in the clinic of the future, close collaboration between researchers, clinicians and policy makers is important to ensure patient protection and the advancement of global health.

References

1. Anguela, X. et al. Entering the Modern Era of Gene Therapy. Annual review of medicine. 70, 273–288 (2019).

2. Li, Y. et al. Ex vivo cell-based CRISPR/Cas9 genome editing for therapeutic applications. Biomaterials. 234, 119711 (2020).

3. Mendell, J. et al. Current Clinical Applications of In Vivo Gene Therapy with AAVs. Molecular therapy : the journal of the American Society of Gene Therapy. 29, 2 464-488 (2021).

4. Cavazzana, M. et al. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nature Reviews Drug Discovery 18 447–462 (2019).

5. Sermer, D. et al. CAR T-cell therapy: Full speed ahead. Hematological oncology vol. 37 1 95-100 (2019).

6. Nuzbrokh, Y. et al. Gene therapy for inherited retinal diseases. Annals of translational medicine. 9 15 1278 (2021).

7. Wirth, T. et al. History of gene therapy. Gene. 525 2 162-9 (2013).

8. Ramamoorth, M. et al. Non viral vectors in gene therapy- an overview. Journal of clinical and diagnostic research. 9 1 (2015).