Given the presently wild excitement being evoked by new breakthrough results in gene-based immunotherapies for cancer, laying the criticism of this article at the door of the gene therapy clinical trials industry might seem misinformed, unfair, or even just plain frivolous. In reality, the concern raised here is far from any of these explanations.

Although the currently accruing remarkably positive outcomes with treatments based on isolation, genetic activation, and treatment with stem cell-enriched or T-cell populations fit well within the new narrative for a finally successful gene therapy industry, genetic immunotherapy is a special case for gene therapy; and even as a special case, it may still fall prey to a long-standing shortcoming in the general approach to gene therapy clinical trials.

There are attitudes seated deeply in the gene therapy clinical trials industry that put its future success at great risk. They are reflected in the basic name of the industry that overlooks a fundamental element of its therapeutic approach. The industry and its practitioners deserve a world of praise for the many technical challenges they have overcome to achieve highly significant improvements in gene transfer efficiency and safety.

However, the rubric “Gene Therapy” fails to acknowledge the therapeutic approach’s major dependence on tissue stem cells. As detailed below, renaming the discipline “Stemgene Therapy,” would be an ideal start for the work of re-inspiring the industry, so that it can begin to configure more effective strategies for accelerating progress for a more complete stemgene therapy narrative.

The Disconnect Between Scientific Practice and Scientific Knowledge

Many factors can result in scientific practice becoming surprisingly disconnected from even well accepted scientific knowledge. Politics, economic factors, and governmental regulatory policy are well-recognized external factors that can be responsible. In the case of Gene Therapy, it appears that internal industry factors are more likely to be responsible for the presently major, industry-limiting disconnection between scientific practice and scientific knowledge.

The essential scientific knowledge is that durable curative gene therapy must, necessarily, also be stem cell therapy. The persistent disconnection in the gene therapy industry is seen by the many clinical trials that proceed without insuring that this knowledge underpins their design. Therapeutic genes are inert unless installed into the expression engines of cells. Because different cells have different lifetimes in the body, the choice of cell for a gene therapy governs how long the introduced genes can be effective.

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With the exception of a few types of specialized mature cells like neurons, the only cell types in organs and tissues that have lifetimes on the order of the human lifespan are tissue stem cells. A gene replacement or gene-editing therapy that does not incorporate stem cell targeting is a gene therapy that is not likely to fulfill its promise of permanent cure. In earlier writings, the author has suggested that this failing may explain the late losses of efficacy in Bluebird Bio’s gene therapy trials.

The ‘Stemgene Therapy’ Consideration

In reality, the stemgene therapy disconnection in the gene therapy industry is not one of knowledge, but instead one of technology. Based on the gene therapy field’s research papers and choices of cell populations targeted in clinical trials (e.g., hematopoietic tissue stem cells), there is good acknowledgement of the importance of tissue stem cells in achieving durable gene therapies.

However, beyond starting with stem cell enriched populations, in which stem cells are still quite infrequent, the industry has largely left the likelihood of stem cell-targeting up to chance. This surprising lack of specific strategy is the really significant disconnection. The gene therapy industry is expending very limited resources on addressing a problem that is rate-limiting for the success of its core therapeutic principle. Basic technologies for identifying, quantifying, producing, and gene-targeting tissue stem cells are still awaiting discovery and development.

This stemgene therapy consideration may also apply to the recent excitement over emerging short-term gene therapies for cancer immunotherapy. Genetically-activated T-cells that kill cancer cells are mature cells that do not self-renew, resulting in short-term therapies without a means for long-term cancer cell surveillance. However, in the future, immunotherapeutic T-cells may be produced from genetically-engineered hematopoietic stem cells or memory T-cells, which could act like stem cells for genetically-activated T-cells. Either stemgene therapy strategy could provide improved cancer immunotherapies with the capability of long-term immune surveillance to prevent cancer recurrences.

Closing the Technological Gap in Gene Therapy

Scientific reconnection of the gene therapy industry to achieve a more apparent stemgene therapy industry may require a change from the traditional nature of the provider-sponsor relationship of the current gene therapy industry. When a knowledge or technological gap is generally recognized as holding up the success and progress of an entire industry, both the providers and the sponsors should look for opportunities to partner in closing the gap.

This approach may require that sponsors invest resources in provider labs for development and applications research. Providers should not wait for sponsors to ask explicitly for help with problems that limit project success. Instead, they should be pro-active in recommending potential solutions or partnering to develop them. In this way, the industry can better meet its overarching charge of bringing safe and efficacious stemgene medicines to waiting patients.



James L. Sherley, M.D., Ph.D.