Slow Progress and a Shaky Start—What’s Next for Gene Therapy?


Gene therapy is showing tremendous promise, with several treatments already on the market and hundreds more at all stages of development. The field had a pretty rocky start, though, and progress has been slow. Despite recent, more rapid advances, concerns and questions remain. What might the future hold?

Shaky Start

The first hint that injecting DNA into human cells could affect cell function was demonstrated in 1971 in a laboratory using human fibroblast cells extracted from patients with galactosemia.1 The concept of delivering a gene therapy to live patients was broached shortly thereafter.2

These initial studies fueled excitement around gene therapy, and more trials were conducted. Optimism and expectations for gene therapy reached unrealistic levels and perhaps led to questionable study designs and procedures.3

When three patients died due to runaway immune responses, the U.S. FDA launched investigations into gene therapy trials.4 Issues were found with the way trials were conducted5 and with the safety of the viral vectors in use at the time.6 As a result, gene therapy development stalled in the early 2000s.

Meanwhile, new trials were conducted in the late 1980s using gene therapies based on viral vectors developed from murine retroviruses. In one trial, white blood cells from patients with advanced melanoma were modified using a retrovirus and the cells were infused back into the patients.7 Children with severe
combined immunodeficiency (SCID) missing the adenosine deaminase (ADA) gene were treated with T cells modified using a retrovirus designed to deliver the missing gene and experienced improved
health.8 Unfortunately, adverse events were observed for gene therapies using vectors derived from murine retroviruses; some of the patients developed forms of leukemia.6

Viral Vector Advances

Some researchers, however, remained convinced that safe gene therapies could be developed. The key was to overcome problems with the first-generation adenovirus and murine retrovirus vector technologies.6 This goal has been achieved through the use of adeno-associated virus (AAV) and lentiviral vectors.

AAV serotype 2, in particular, was found to be effective for transferring genes in vivo with minimal inflammation or activation of immune responses, as well as persistent and able to express the transgene for the life of the target cell.6 Wild-type AAVs do not cause diseases in humans and can be engineered for specific cell or tissue types.4 Early AAV vectors have already been improved by using AAV capsids from primates.6 AAV8 and AAV9, for instance, have higher transduction efficiencies and reduced immune responses; AAV9 can also cross the blood–brain barrier.

Lentiviruses, such as HIV, infect non-dividing cells. Replication-incompetent lentiviral vectors cannot spread the virus but allow for high transduction efficiencies.6 In addition, these self-inactivating (SIN) vectors contain insulator sequences that prevent vectors from activating oncogenes from their host cells.9

More recent developments have explored leveraging recombinant AAV vectors to deliver synthetic microRNA (miRNA) for the downregulation of gene expression to treat diseases caused by undesired additional gene function rather than loss of genes or gene activity.10

The Current Landscape

Improvements in the safety of viral vectors have had a dramatic impact on the gene therapy sector. By the end of 2017, more than 2,400 gene therapy clinical trials had been conducted.11 Most were phase I studies, and the majority addressed oncology indications, followed by monogenetic diseases (often rare) caused by problems with a single targetable gene.

In just the last few years, six gene therapies have been approved in the EU, and several have also reached the market in the United States. Approximately 750 gene therapies are in clinical development today, and by 2025 the FDA expects to approve 10–20 new cell and gene therapies annually.12

Gene therapy clinical trials are currently evaluating treatments for SCID, eye diseases, HIV, sickle cell anemia, cystic fibrosis, congestive heart failure, hemophilia, cancer and various other genetic disorders.13 Numerous chimeric antigen receptor (CAR) T cell therapies — in which viral vectors are used to generate CAR receptors on patient T cells, which are then infused back into the patient — are also in clinical trials targeting various types of cancer. In 2018, 255 companies were developing gene therapies — up from 69 in 2014, according to the Alliance for Regenerative Medicine.13

The Potential of Non-Viral Gene Transfer

Given the safety issues associated with first-generation viral vector technologies, it is not surprising that some research efforts are focused on the development of non-viral methods for delivering gene therapies. In addition to avoiding the potential for immune responses, technologies, such as injection of naked DNA, electroporation, sonoporation, magnetofection and the use of oligonucleotides, lipoplexes, dendrimers or inorganic nanoparticles, may also be more amenable to large-scale production.10

Many of these approaches, however, suffer from low transfection efficiencies and require further development, although most have been used in some clinical trials. Two that have received significant attention include direct injection of DNA (or RNA) plasmids, most often into muscle, and lipofection, which involves the use of DNA plasmids surrounded by cationic liposome to facilitate delivery into cells.5

The Power of Gene Editing

The advent of gene-editing technologies has opened up whole new avenues for gene therapy development. Engineered nucleases, such as transcription activator-like effector nucleases (TALENs) and zinc finger nucleases (ZFNs), were the first to garner attention. The simpler and more precise CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system, however, appears to have the greatest potential.

Nucleases are enzymes that can insert, delete or replace DNA. TALENs and ZFNs are engineered restriction enzymes designed to bind and cut specific sites within the genome. The CRISPR gene-editing tool was developed from a natural system that affords bacteria protection against viruses. A guide RNA (gRNA) tells the Cas9 enzyme which part of the viral DNA to remove. The system has been modified to enable directed editing within all types of cells, including those of plants and mammals.

Unlike traditional gene therapies, which introduce a functional copy of missing or damaged genes, gene editing is intended to alter DNA in order to remove or modify dysfunctional genes. It thus has the potential to be applied to a wider array of genetic disorders.4

Many versions of CRISPR have and are being developed today, and these various approaches are being applied to the development of gene therapies and diagnostics. A few of these gene therapies have entered clinical trials. One example is a treatment for beta-thalassemia and sickle cell disease under development by CRISPR Therapeutics and Vertex Pharmaceuticals.

The Pricing Dilemma

A discussion of the history and state of gene therapy would not be complete without touching upon the issue of pricing. Gene therapies are tremendously expensive. In May 2019, AveXis, a Novartis company, received FDA approval for Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy for the treatment of pediatric patients with spinal muscular atrophy (SMA). Zolgensma carries a price tag of $2.1 million per patient.

The number is shocking, but it must be remembered that gene therapies often can cure diseases, not simply treat them. Organ transplants, which are considered curative procedures, are also expensive, costing several hundred thousand to more than a million dollars.12

The total cost of treatment for many diseases that might be cured by gene therapies can, over the lifetime of the patient, often exceed the cost of even a highly priced gene therapy like Zolgensma. For patients suffering from chronic diseases with high treatment costs, such as sickle cell disease or cystic fibrosis, even high-cost gene therapies could provide an economic advantage, in addition to eliminating years of suffering.14

The annual treatment cost for patients with SMA is $100,000–150,000, which can add up to more than $2 billion over a lifetime.15 Novartis has established a payment plan with insurance companies that is tied to the performance of the therapy.

The cost of developing gene therapies is also significant. Given the safety issues encountered early on in the field, it is not surprising that extensive safety studies are required. Even if a viral vector has been previously used in an approved gene therapy, safety studies must still be conducted for any new developmental gene therapy using that vector.14 The watchword is “caution.”

Many Other Hurdles to Face

Questions about pricing are not the only challenges that must be overcome if the gene therapy field is to continue its rapid advance. There are also many technical hurdles.

The persistence of gene therapy treatments must be increased to ensure that they provide the desired therapeutic effect throughout the lifetime of patients. Further advances in nonviral gene delivery are needed to completely avoid the potential for immune responses. Technology that enables the development of gene therapies targeting multiple genes is needed in order to treat diseases that are driven by multiple dysfunctional or missing genes, such as Alzheimer’s disease and diabetes.16

In the short term, there is a fundamental need to establish robust, reliable and readily scalable processes for the GMP manufacture of viral vectors and to install more production capacity so that approved treatments can reach the market as quickly as possible. During development, most gene therapies have been produced in the lab using small-scale equipment that is operated manually and is not practical for larger-volume manufacturing. Equipment suppliers have made progress in developing bioreactors and downstream processing systems amenable to vector production, but more work needs to be done.17


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Nigel Walker

Mr. Walker is the founder and managing director of That’s Nice LLC, a research-driven marketing agency with 20 years dedicated to life sciences. Nigel harnesses the strategic capabilities of Nice Insight, the research arm of That’s Nice, to help companies communicate science-based visions to grow their businesses. Mr. Walker earned a bachelor’s degree in graphic design with honors from London College of Communication, University of the Arts London, England.