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Gene therapy

When will it deliver?


The concept of gene therapy has been around for decades; with over a quarter of a million peer-reviewed publications generated, careers made and retired from, and hundreds of biotech companies coming and going in that time. However, this vast investment in time, human resources and money has yet to deliver significant direct patient benefit and still remains more of a promise for the future, rather than a medicine of today.

This raises the following questions:

  1. Why hasn’t the research translated to mainstream patient benefit?
  2. How are these limitations impacting current gene therapy programmes?
  3. What is the roadblock to gene therapy?
  4. Will gene therapy ever fulfil its promised potential?

The early years

The brief answer to question number one is: a combination of over-ambition and naivety about the target, accompanied by a lack of resources and enthusiasm for understanding and overcoming the major hurdle of delivery.

In the early nineties, as the concept of gene therapy was taking hold, scientists and pharmaceutical companies could only see the upside of how gene therapy would offer a precision medicine option for all diseases. These early pioneers were largely focused on DNA-based gene delivery or the use of DNA anti-sense technologies to specifically inhibit mRNA translation.

In oncology, there was already a plethora of seemingly obvious targets, as our knowledge of oncogenes driving different cancers expanded. However, with hindsight, many basic questions were ignored, such as what percentage of cancer cells would have to be transfected for the therapy to work? Would there be off-target effects? Or challenges of tumour heterogeneity? And how easily would resistance to such an overtly targeted therapy arise? While these questions are applicable to all types of therapy, when combined with the experimental delivery vectors and the associated lack of pharmacokinetic/toxicology knowledge of these vectors, they ensured that the promise of gene therapy in the early nineties could not be remotely met.

The over-simplification of gene therapy, personal ambition and a rush to clinic and commercial competition had tragic consequences, with the death of Jesse Gelsinger in 1999 being attributed to the viral vectors used in the trial. Because of his death, 652 previously unreported, serious adverse events, including deaths, were reported to the US National Institute of Health. As many of these trials were performed on very sick patients, it is unclear how many of these events can be attributed to the gene therapy itself. However, the culture of secrecy, corner-cutting and late reporting further undermined this dawning technology.

These tragic outcomes, coupled with the realisation that gene therapy was not a ‘quick-fix’ for all diseases, led to a downturn in the enthusiasm for gene therapy trials and research, which has only started to recover over the last decade.


Renewed interest in gene therapy in recent years has been driven by new, basic biology discoveries. From a payload perspective, these include new technologies such as siRNA, Sleeping Beauty transposases, CRISPR-Cas9 gene editing, ARCUS gene editing, nucleic acid vaccines, oncolytic viruses and chemically modified mRNA. These new capabilities, together with improved delivery vehicles, offer fresh hope to fulfilling at least some of the early promise of gene therapy.

However, despite the improvement in both viral and non-viral (primarily liposomal) delivery vectors, the recurring delivery roadblock for gene therapy remains, imposing constraints on its widespread use. However, this time, these constraints are largely self-imposed, with companies limiting their pre-clinical programmes to targets currently accessible to existing vectors.

This is reflected in the large number of companies focusing on liver disease, as liposomal delivery vehicles tend to accumulate in the liver, or where the mode of delivery offers targeting capabilities for viruses, such as ocular and ex vivo therapies. While this more realistic approach is favourable compared to the early ‘gold-rush’ days of gene therapy, it potentially confines gene therapy to the rare disease sector and not mainstream therapeutics. This is reflected in the attitude of some blue-chip pharma companies. One company, for example, is not seeking new delivery vectors as it is happy with viral delivery for its rare disease programme - the implication being that this is the only space the company sees for gene therapy. In order to move gene therapy back to the mainstream, the roadblock of delivery must be faced head on.


Liposomes remain the backbone of non-viral delivery. There are many valuable biotech companies out there with brilliant science and great targets, but which are essentially in the clinic with ancient, simplistic liposomal delivery vehicles, often traceable to generic formulations that are over 10 years old. Liver accumulation, lipid-mediated toxicity and lack of targeting remain hurdles that liposomes are yet to fully clear. In contrast, viruses still seem to be the obvious choice, as delivering nucleic acids into cells is what they do. However, the pathogenic origins of viral vectors and associated immune response mounted against them is their biggest limiting factor as it precludes regular or even repeat dosing. This exacerbates the challenges of gene therapy further, as therapies/payloads must be designed to largely work as a one-hit treatment. Additionally, despite decades of complex viral molecular biology research, toxicity, payload limitations, inability to target different cell types, manufacturing and regulatory complexities further stymie their use beyond ex vivo and niche targets.

The overt focus on liver disease has led to one new system for delivering siRNA to the liver, called GalNAc. GalNAc uses a specific sugar group attached to chemically-modified siRNA to target liver cells. GalNAc technology does hold potential, but has limited utility, and a recent trial suspension using this technology has not yet been fully resolved.

Therefore, the use of sub-optimal delivery vectors may continue to result in disappointing trial data and further hinder gene therapy. Despite Jesse Gelsinger’s death being over 18 years ago, unexplained deaths have occurred in recent gene therapy trials and a decade of progress could still be hampered by using ill-conceived or poorly-understood delivery vectors. Delivery remains the biggest barrier to gene therapy.

Future prospects

To ensure that the promise of gene therapy can be fulfilled, investment in new gene therapy delivery technologies needs to be raised. As do their profiles, to escape the negative connotations of ‘standard’ drug delivery/platform companies. Cracking gene therapy delivery is very different from marginally improving the pharmacokinetics profile of an existing drug with a new delivery platform.

Looking to the future, there is exciting progress being made with nucleic acid vaccines, where the bar of efficiency of transfection and targeting may be lower. Yet there is still room for improvement. Some companies are investing in liposome development, but this needs to become far more systematic, along the lines of big pharma’s small-molecule programmes, in order to identify new lipid combinations that are capable of matching the best viral platforms and that are safe and simple to manufacture.

Finally, looking beyond liposome versus viral delivery, alternative technologies such as new polymers, conjugates, vesicles, dendrimers and peptide nanoparticles, such as LipTide (an ‘artificial virus’), urgently need investment and further evaluation. A safe, simple-to-manufacture, non-immunogenic and targetable vector with payload flexibility remains the holy grail for gene therapy delivery. In the meantime, a more flexible ‘mix-and-match’ approach using existing and newly developed technologies optimised for specific targets remains the best way forward.

In summary, if expectations are managed and investment made in the fundamentals of delivery, gene therapy can emerge as far more than just a niche player, but rather as a mainstay of therapeutic approaches for a wide variety of common diseases.

Article by
Dr Simon Newman

is director of pre-clinical research at Nanogenic Solutions

3rd November 2017

Article by
Dr Simon Newman

is director of pre-clinical research at Nanogenic Solutions

3rd November 2017

From: Research



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