Abstract
Regular readers of Human Gene Therapy may notice a similarity between the title of this editorial, looking ahead to 2019, and that from the December 2018 issue, looking back at our top five most cited papers of the previous year. While December's effort was based on valid citation data, the current effort is fraught with all of the limitations inherent in forecasting future events. Thus, it is likely to include some predictions that will prove to be inaccurate. Given this caveat, a consideration of what events may transpire in our field could still prove to be a useful exercise.
The continued rapid progress of human gene and cell therapy in the latter half of the 2010s is fueled by the maturation of gene and cell therapy platforms, improvements in manufacturing capabilities, and an investment climate in the United States and Europe that has been very favorable to biotechnology and pharmaceutical industries engaged in gene therapy product development. Many of these factors are likely to continue in 2019, although some of them may bear further examination. Given what is known in late 2018, the following predictions are put forward for consideration.
1. Clinical successes in gene therapy will be consolidated and expanded upon in related clinical areas. Headlines of the past 2 years in the gene and cell therapy fields have led to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensure of several human gene therapy products, including recombinant adeno-associated virus (rAAV)-based gene therapies for lipoprotein lipase deficiency and inherited retinal dystrophy due to RPE-65 mutation (IRD-RPE65), 1,2 ex vivo retroviral hematopoietic stem-cell (HSC) gene therapy for genetic immune deficiency, 3 and ex vivo lentiviral gene therapy to create chimeric antigen receptor (CAR)-T cells to treat CD19+ cases of leukemia and lymphoma. 4,5 Likely follow-ons to these approvals could include clinical trial efficacy demonstrations and/or regulatory approvals for rAAV-based gene therapies for other disorders of the neuro-retina or central nervous system, such as spinal muscular atrophy, or of the musculature. 6 Similarly, one may anticipate the use of ex vivo HSC transduction for other genetic disorders of the immune system or hematopoietic system, such as hemoglobinopathies. Finally, efforts abound to expand the CAR-T cell approach to target other tumor-specific epitopes in different malignancies. The momentum behind this trend seems so overwhelming at this point that one may consider this prediction as a relatively safe one.
2. Clinical applications of human genome editing will continue to mature. A number of nuclease systems, including Zn-finger nucleases, TALENs, and meganucleases, have been developed that are capable of sequence-specific in vivo double-strand DNA breaks based on protein–DNA interactions. The development of CRISPR-Cas9-based genome editing in 2012 has revolutionized this field, however, because it has allowed for enabled RNA-sequence, guided DNA editing, with only a modest degree of restriction based on the presence of a protospacer adjacent motif (PAM sequence), specified by the sequence 5′-NGG-3′. 7 While this tremendous power of this technology has been widely recognized, a handful of gene editing–based products are being developed for clinical applications, including ex vivo HSC correction, T-lymphocyte engineering, and in vivo genome editing of the retina and liver.
3. Public scrutiny of the costs of expensive molecularly targeted therapies will intensify. As more gene therapies are marketed in the United States and Europe, it has become clear that the unit costs of such therapies will be among the most expensive of FDA and EMA licensed products. As has previously been discussed by this editorial team and many other commentators, the annual cost of gene therapies is likely to be similar to other technologically intensive therapies, such as enzyme replacement therapies and precision small-molecule therapeutics, with annualized costs between $200,000 and $500,000 per year. 8 Increasing public debate about the appropriateness of such pricing and the adverse effects of such pricing on global health equity could indicate future difficulties with insurance reimbursement for such pricing, which could itself contribute to broader chilling effects on biotechnology and pharmaceutical company investments. 1,9
4. The economic and policy effects of protectionist trade policies in the United States could adversely affect the investment climate for biotechnology in general and gene therapy in particular. The prediction of trends in the financial markets is far beyond the scope of this journal or its editorial staff. However, it is worth noting that the Nasdaq Composite, on which most U.S. and many European gene therapy companies are listed, increased by 3.3-fold from September 2008 to September 2018, climbing from 2,418.21 to 8,062.44. 10 However, recent trends have been negative, with the Nasdaq Composite dipping back below 7,000 at the time of writing, and many experts anticipating an ongoing negative trend because of the chilling effect of trade disputes between the United States and many other nations, including China and the European Union.
5. Uncertainty about the future of public funding for biomedical research could undermine efforts to enhance the development of new gene therapy scientists within academia. The budget of the National Institutes of Health (NIH) has continued to grow steadily during the Trump administration, in spite of initial threats to cut funding up to 20% and to restrict or eliminate indirect cost funding on NIH grants. 11 These threats have led biomedical research PhDs increasingly to seek professional career development to prepare them for careers in industry or in roles other than that of being independently NIH funded, tenure-track university faculty. 12 From a student's perspective, such trends are not necessarily positive or negative. However, from the perspective of universities in general and U.S. medical schools in particular, such trends could narrow the talent pool of scientists engaged in translational research of molecular therapies.
Overall, we remain very optimistic about the future of gene therapy in the near term, but more guardedly so with respect to the longer term. The science and clinical practice of gene therapy are continuing to advance at the fastest pace in its history. We sincerely hope that future headwinds created by potential future challenges to both private and public investment and to the recruitment of biomedical scientists to academic gene therapy research do not interfere with the gene therapy field having its broadest possible positive impact on those patients and families who have waited so long for their specific diseases to be effectively treated. This journal will continue to be dedicated to that cause, regardless of how cycles of positive and negative external factors affect the gene therapy landscape.