Gene therapy – the status quo and future trends

The uptick in recent approvals in the gene therapy space is emblematic of a field which is now coming to fruition, and the wave of clinical trials in progress provide an insight into the current trends that will shape the field as we look toward an era where gene therapies are likely to become an increasingly well-established treatment modality.

Gene therapies to date

Gene therapies encompass the introduction, removal, or change in the content of a patient’s genetic code with the goal of treating or curing a disease. Types of gene therapy include “in-vivo” gene therapies, in which genetic intervention occurs inside the body of the patient, for example by injecting the patient with vectors which mediate the introduction of a genetic sequence or gene editing apparatus into target cells in-vivo. Alternatively, “ex-vivo” or “cell-based” gene therapies use modified cells containing an active ingredient synthesized following vector-mediated introduction of a genetic sequence into target cells ex-vivo, and (re)insert those cells as the therapy.

The first gene therapy, Glybera, launched in Europe in 2012 for the treatment of lipoprotein lipase (LPL) deficiency in patients with severe or multiple pancreatitis attacks, an ultra-rare disease which affects only about 1 person in a million. Since then, the progress in this field has been exponential, and, despite the expiry of Glybera’s marketing authorisation, the recent approval of Elevidys by the FDA has taken the number of gene therapies approved in the US and/or EU to 19 at the time of writing. Of these, 10 were approved in the last three years (Tables 1 and 2).

The products listed above have provided potentially curative treatment options where none existed before, transforming the lives of patients with these disorders. However, the eye-watering prices of the therapies in the recent flurry of approvals has inevitably caught the attention of the media. In September 2022, Bluebird Bio's Skysona (priced at $3 million per treatment in the US) became the most expensive therapy in the world, replacing Novartis' AAV-based gene therapy for spinal muscular atrophy, Zolgensma (priced at $2.1 million per treatment).

Broadening horizons beyond rare disease

It should also be noted that, to date, all of the approved therapies have been targeted towards rare and ultra-rare conditions, something which is expected to change looking forward.

There are two different gene therapies for sickle cell disease expected to receive regulatory decisions later this year (Lovo-cel; formerly BB1111 and Exa-cel; formerly CTX001), with several more gene therapy clinical trials for this disease already underway. A genetic blood condition caused by a single mutation in a well-studied gene, sickle cell disease represents an ideal candidate for gene therapy. About 100,000 people have this disease in the US alone, meaning this disease has a significantly larger patient population in comparison with the diseases targeted by previously approved gene therapies in Table 1 above. The upcoming regulatory decisions for sickle cell disease exemplify the expansion in the scope of the gene therapy field to more common diseases as we look to the future. While this represents a positive step towards delivering the promise of gene therapies to a broader patient population, concerns have been raised over patient access in view of the high cost of gene therapies. Some estimates have predicted that gene therapy products for sickle cell disease will cost $1 million for a one-time dose – a high up-front cost, but one that must be weighed against the cost of long-term management of the disease.

It remains to be seen how payers, who so far have broadly accepted the high costs for rare and ultra-rare conditions, will respond to any potential approvals of gene therapies for more common indications. What is undoubted is that the cost, combined with an exponentially increasing patient population will present a unique challenge to healthcare systems to ensure that all patients, not just those with financial means, can benefit from these innovative therapies.

There has also been a shift towards targeting more complex, polygenic diseases within the prevalent disease category, noted by the Alliance for Regenerative Medicine, who observed that within central nervous system disorders, there has been a gradual shift from disorders such as spinal cord injury, traumatic brain injury, and neuropathic pain to more complex, polygenic disorders, including Alzheimer’s disease, autism, and even treatment-resistant bipolar disorder and depression.

The first approval for a gene therapy for a prevalent disease in the United States and Europe could be on the horizon, with Phase 3 programs in indications including critical limb ischemia, congestive heart failure, diabetic peripheral neuropathy, and macular degeneration currently in progress.

The rise of CRISPR

In addition to the diseases being targeted, there has also been a shift in which in gene editing technologies are being used.

While zinc finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN) were the editing technologies used to set the scene for gene editing, in recent years CRISPR has overtaken them to become the dominant approach. This is reflected in the clinical pipeline, where the total number of TALEN and ZFN trials has dropped by 41% since 2017, according to the Alliance for Regenerative Medicine. In fact, the number of clinical trials using CRISPR is now more than double the number of clinical trials using TALEN, ZFN, and other gene editing methods combined. In addition to in-vivo gene therapy, CRISPR has been widely adopted by developers in the ex-vivo, cell-based gene therapy space and used to devise improvements to CAR-T, Natural Killer, and other cell therapies that target different cancers.

Exa-cel, the CRISPR therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics to treat sickle cell disease, is up for approval this year in the US, EU, and UK. This is the first regulatory decision for a CRISPR therapy – an exciting milestone for the gene therapy field as a whole, and one that remarkably comes just over a decade after Jennifer Doudna and Emmanuelle Charpentier published their ground-breaking paper in Science.

Not limited to blood diseases, the gene therapy field is progressing different applications of CRISPR to treat a variety of diseases. For example, in November 2022, CRISPR Therapeutics shared preliminary results from a trial using their allogeneic CD70-targeting CAR-T cells in individuals with solid tumors in the kidney that are not being effectively controlled with standard therapies. The treatment was well-tolerated and without serious side effects. The treatment achieved a 77% disease control rate and at the last update, one participant no longer showed any signs of disease.

In the past year, Intellia also provided exciting results hinting at the promise of CRISPR as a therapeutic platform technology in the clinic. Following the groundbreaking results of their NTLA-2001 hATTR amyloidosis therapy, Intellia targeted angioedema with NTLA-2002, but remarkably did so without changing the lipid nanoparticle, the Cas9 mRNA, or the method of delivering the treatment from NTLA-2001. All that changed was 20 nucleotides of the guideRNA, and the result was a medicine for a different disease – underlining the advantageous ease of programmability which has propelled CRISPR to dominance.

The toolbox of different types of CRISPR-based genome editing available to researchers is also expanding. In 2022, Beam Therapeutics’ therapy for sickle cell disease and Verve Therapeutics’ therapy for heterozygous familial hypercholesterolemia started clinical trials. These trials are the first to use a novel base-editing approach - a type of CRISPR-based editing that can achieve precise modifications to single nucleotide changes in a sequence without causing double-strand breaks in DNA and may be safer for use in humans. Base editing is also being harnessed for the development of cell-based therapies, as evidenced by AstraZeneca’s recent licensing deal with Revvity to use their Pin-point^TM base editing platform.

Prime editing, another CRISPR-based technology which also makes edits without double-strand breaks and can edit longer lengths of DNA is also being developed for the clinic. Similarly, CRISPR-based epigenome editors that alter the expression level of a protein from a targeted gene rather than making edits to the DNA sequence itself, are advancing towards clinical use. These new tools will broaden the range of disorders that can potentially be treated using CRISPR-based technology.

Conclusion

The clinical trials in this space show a trend towards addressing wider patient populations, enabled by the expansion into new therapeutic areas partially driven by the ever-enlarging CRISPR toolbox. Broadening the addressable population presents significant hurdles in terms of ensuring patient access to gene therapies, but the aim of delivering on the promise of gene therapy across a broad spectrum of diseases is now firmly in sight.