A revolution in medicine

These are heady times for gene therapy, yet we have a long way to go before it achieves its promise. It is, to use an historical analogy, much like where aviation was in the first decade or two of the 20th century.
Aviation has a fascinating and ironic history. It was in 1895, only 8 years before the Wright brothers proved him wrong, that the world’s most eminent physicist, Lord Kelvin, proclaimed that heavier than air flight was impossible. He knew a great deal about gravity, a great deal about air pressure, but next to nothing about aerodynamics. Nor did anyone else, to be fair about it. Even the Wright brothers were constantly tinkering and experimenting as they tried to gain an understanding of the earliest form of aviation. As it was, and despite Lord Kelvin’s dictum, they only succeeded for perhaps 20 seconds of powered flight.

Twenty seconds that created a new world.

It was another decade before the world’s first commercial flights – which failed. It took three decades before the world’s first trans-Atlantic commercial flights – which succeeded, but even then they were unpressurized and vomit bags were ubiquitous for good reason. Yet now, despite occasional failures and disasters, we have come to regard safe and relatively comfortable commercial flights around the globe as routine parts of life in the 21st century.

Gene therapy has been off to a similar start. Despite early deaths two decades ago, despite hesitation and concerns, we are beginning to see “successful flights” as gene therapy comes into its own. Just as with those first trans-Atlantic flights, we see discomfort and risks, yet we also see a way to cross the wide oceans of human disease and land safely – if still a bit shaken – on the other side of clinical cures.

Recently, I chaired a global conference on gene therapy and I opened the conference by pointing out three areas of concern:

1) Technical issues. We still know so little, much as the Wright brothers did in the first few years. They were constantly changing configurations, much as we are still rapidly trying to understand new viral vectors, new serotypes, new promoters, lipid nanoparticles, mRNA, cassette interactions, and gene editing, while we are still dealing with immunogenicity, toxicity, and production issues such as costs, timing, quantity, quality, and CMC issues generally. Gene therapy is moving too fast for any of us to know what the technology will look like in ten years.

2) Financial issues. The market for rare diseases is narrow, yet these indications are currently the bulk of new FDA applications, and this issue is a major long-term concern in the board rooms of those vendors who are producing tomorrow’s gene therapies. It is hard to find a viable long-term commercialization model when your patient population is fewer than 20,000 patients per year in the US for SMA, or where we routinely identify only a few dozen patients per year globally as in Hutchinson-Gilford Progeria. How can we afford to do the R&D and still afford to treat patients who need gene therapy? We can, but it will take not merely compassion, but a great deal of thought and hard work to succeed.

3) Conceptual issues. There are conceptual surprises that are yet to be explored. Despite finally sequencing the entire human genome, we currently focus almost exclusively on protein-encoding genes which make up only 1.2 % of the human genome, rather than regulatory elements which (whether we mean genes, sequences, or other elements) encompass as much as 40% of the genome. We need to avoid letting ourselves assume that the only interesting targets are in the protein-encoding genes. It’s a dangerously naïve assumption, one we would do well to avoid.

While all of these points concern us here at Telocyte, it is the final point – the conceptual revolution that most people are still unaware of – that concerns us most. While the microbial revolution changed the history of medical care, it is the aging revolution, that is about to change global medicine in the next decade. (I will be chairing the June 2022 conference on Longevity Therapeutics in San Franciso, as well as giving the closing keynote address, and a preconference workshop.)

Rather than dealing with single gene diseases, we are moving toward an understanding of patterns of gene expression – epigenetic therapy – that will entirely alter our view of aging and age-related disease.
And like that first flight at Kitty Hawk, it will change the world.