Standing On The Shoulders Of Stem Cell Gene Therapists: History, Hyperbole And Hope For The Future

Posted July 7th, 2016 by Jason Gardner, in From The Trenches, New business models

This post was written by Jason Gardner, Atlas EIR and CEO of Magenta Therapeutics, as part of the From The Trenches feature of LifeSciVC.

A new type of medicine was approved in Europe at the end of May that culminated from the successful convergence of two fields of science: stem cell transplantation and gene therapy. Strimvelis, a patient-specific gene-modified stem cell medicine for ADA-SCID (a fatal immunometabolic disorder similar to the bubble-boy disease), was developed by scientists at the San Raffaele Hospital and Telethon Institute (TIGET) in Milan, then later partnered with GSK. The journey took over 25 years of dedicated work from many groups and involved a pivotal trial with 12 children and their brave families. I was fortunate to be involved on the GSK side of the TIGET alliance from 2010-2015, building upon my previous experiences in gene-modified stem cells during a post-doctoral fellowship in the mid-1990s and at Chiron, which had acquired Viagene, an early gene therapy biotech. I thought it was timely to pick out a couple of observations from the development of Strimvelis to see how these might apply not only for the future of stem cell gene therapy but also be the shoulders for the adjacent CAR-T and gene editing technologies to stand on.

I have framed this analysis around the Gartner Hype-Hope curve which traces the evolution of a new technology trigger and has been applied across tech and biotech sectors. The Hype-Hope curve predicts a 20-25 year journey through a peak of inflated expectations, trough of disillusionment (a.k.a. the Valley of Death), slope of enlightenment to a plateau of productivity (Figure A).


A brief retropsective of the key inflection points in stem cell gene therapy map closely to this curve (Figure B).


Stem Cell Gene Therapy Technology Trigger was Pulled in T cells

ADA-SCID was considered the ideal target for gene therapy because the genetic basis of the disease was understood; the disease could be corrected by gene modification in preclinical models; and production of normal protein at low levels from corrected cells conferred a survival advantage. It was the first disease targeted in gene therapy trials which started at the NIH in 1990 with two children using gene modified T cells. The results were encouraging, but clinical effects lacked durability with low expression of the corrected enzyme due to lack of gene transfer efficacy in long-term progenitors. 

Stem Cells Ascended to the Peak

Parallel work at the San Raffaele Group focused on CD34 stem cell gene therapy, and clinical trials commenced in 1992. Data slowly emerged from this academic trial showing improvement in patients over the next 5-8 years, and by 2000, expectations were rising in the broader gene therapy field as other groups enrolled patients on trials in more diseases, including cystic fibrosis, hemophilia. An expanded array of directly-delivered vectors including adenovirus, AAV and plasmid DNA was being deployed by academic and industry groups as expectations peaked.

Safety Issues Lead to a Trough of Disillusionment

From 1999-2001, safety results from stem cell gene therapy trials in other diseases, including X-SCID, during the same period together with the death of a patient in an adenovirus gene therapy trial of a rare liver disease would put the brakes on new advances. Clinical holds and stringent safety requirements for gene therapy preclinical studies were shadowed by a sharp withdrawal of many industry groups, including my former company, Chiron. The field retreated to its academic base for much of the next decade.

Efficacy Rises on the Slope of Enlightenment

In 2009 the ongoing ADA-SCID trial at San Raffaele Hospital showed that stem cell gene therapy delivered clear disease-modifying benefits in 10 children with a new, durable immune systems. This was published in a landmark paper by the New England Journal of Medicine (here) .

2009-2010 proved to be pivotal to stem cell gene therapy renaissance, with French investigators reporting positive results from patients with adrenokeukodystrohy and beta-thalassemia, which in turn would catalyze Third Rock Ventures to create a new biotech, bluebirdbio, from its earlier incarnation, Genetix, to drive this work forward. Importantly, the new results were based on lentiviral vectors from much earlier work at Cell Genesys and demonstrated the ability to transduce the non-dividing CD34 stem cells with a more efficient gene insertion mechanism and perceived safety profile over many of the previous retroviral vectors.

Productive Stem Cell Gene Therapy Development

As bluebirdbio advanced, GSK would enter the field in 2010 as the first pharma company to drive the late stage regulatory study and ADA-SCID filing in partnership with the San Raffaele/TIGET group and also build out a platform on lentiviral stem cell gene therapy with multiple gene therapy programs. There have been positive data reported from ongoing stem cell lenti gene therapy trials in sickle cell disease, beta thalassemia, Wiskott-Aldrich syndrome, MLD, that provide a sustainable plateau for productivity.

Stem Cell Gene Therapy Learnings and Challenges

As stem cell gene therapy endured the Hype-Hope cycle through the past 25 years, there are several learnings and challenges ahead:

  1. Outside-in innovation laid the basis of the stem cell gene therapy field, with collaborative work across the same academic groups spawning the CAR-T and gene editing areas. Academic physician-scientist pioneers would scramble for grant-funding to propel the science to the clinic with a strong patient-centric pull. These teams would persevere and prevail over technical and safety challenges, with much of the work conducted beyond industry walls. See here for broader commentary.
  2. Pricing and reimbursement will be lightning rods for the sector. Clinical value is clear but these medicines are expensive to make, and the pharmacoeconomic equation will showcase these challenges. Strimvelis will set the benchmark as a potentially curative medicine that others will be measured against. The pricing debate for single-use medicines with curative-intent will be robust with patients central and European healthcare systems, companies and future investors keen participants. One hopes that the Brexit decision will not impact the ability of GSK to provide the medicine via the single center in Italy as patient access, especially in the ultra-rare disease space for stem cell gene therapies in the future, will continue to drive outcomes. (Link to paper)
  3. Continued safety obstacles will remain for gene therapy as vector development evolves. The use of lentiviruses has increased dramatically over the past 5 years as the vector of choice for introducing genes into non-dividing cells, but less than 200 patients have been treated with stem cell gene therapies to date. Methods for detecting and potential removal of deleterious integration site mutations have improved and are likely to be standardized for long-term monitoring.
  4. Infrastructure is expensive to develop for vector manufacture, cell modification, and distribution to global transplant centers, therefore we might expect a shared network system between companies in the cell therapy, CAR-T cell and gene therapy spaces looking to balance investment and risk across diseases and geographies.
  5. The preparation regimen for patients undergoing stem cell transplants remains highly challenging with many toxicities and side effects. The ADA-SCID trial was successful in part because a relatively mild conditioning was applied as only a small amount of “space” was required in patients’ bone marrow to enable a successful transplant due to the survival-advantage of the corrected cells. To extend the diseases for stem cell gene therapy, continued innovation will be needed to hurdle this barrier, particularly in earlier stages and non-fatal diseases (eg sickle cell, beta thalassemias).

The follow-on cycles of CAR-T and Gene Editing

Applying this approach to CAR-T and gene editing fields that have developed on the shoulders of the stem cell gene therapy giants is speculative, as these fields are a long way from an approved medicine and one suspects that there are several oscillations in their curves to come.

With a quick crack of hindsight, we know that the CAR-T work was initiated with first generation zeta-chain TCR work in the mid-1990s focused on T cell modification, with Cell Genesys again an early mover, and this built on the earlier efforts on tumor-infiltrating lymphocytes at the NIH. Unfortunately, the dose of modified cells together with the first-generation construct combined to be a stumbling block with disappointing clinical results. The field would be confined to the academic world with optimized costimulatory vectors (second and third generation CAR-T) until 2010, when the U. Penn group published exciting clinical results with lentiviral vectors that would be licensed by Novartis in a major deal. With clinical data and the entry of a significant oncology-committed pharma, multiple companies would rise up in this hot field. Today, there are dozens of clinical trials, multiple CAR-T CD19 programs and the early-IPO’d companies (Juno, Kite, Cellectis, Kite) have a combined market cap of approximately $13B in advance of approved medicines. The outstanding early results in cancer patients with B cell tumors have been repeated and expansion into solid tumors has driven up expectation, though real challenges remain on safety, durability of tumor response, breadth of disease application and it will be interesting to watch the infrastructure and pricing debates evolve. Therefore, we might conclude that CAR-T field remains on the upswing of expectations as it navigates the clinical execution phase, and it will be fascinating to see the true breadth of application across different tumor types and the safety profile as the curve unfolds.

Gene editing also has a long history, originating in zinc-finger modification of the genome in 1996. Sangamo has been a pioneer with this technology and demonstrated broad success at selective modification of multiple genes with this technology as a research tool.  Early trials with direct delivery for pain were not successful, and some of the hype waned for the field to experience its first dip. Soon after, Transcription Activator-Like Effector Nucleases (TALENs) would emerge as a designer nuclease and energize the field by offering potentially more efficient and selective scissors for DNA-cutting. However, the field moved to T cell based applications with Sangamo advancing next generation zinc-finger nucleases (ZFNs) for HIV infection into the clinic, soon followed by Cellectis who would treat a cancer patient with a CAR-T modified by TALENs in 2012. Accelerating this peak of expectation for gene editing was the advent of CRISPR/Cas9 technology which offers a potentially more efficient DNA scissoring and has caused a significant leap in both publications and media interest. The hype curve now diverges from the traditional curve with the promise that CRISPR/Cas9 will birth medicines for multiple diseases. The combined value of the first two publically traded biotechs, Editas and Intellia, in this area has reached more than $2B with all programs in preclinical development.

The hope of gene editing technology has captured the public and investor base alike, particularly the application of CRISPR/Cas9. Zinc finger, TALEN, and CRISPR technologies will likely progress to the clinic on the back of T cell trials, as has been the case for stem cell gene therapy and CAR technology. In fact, U Penn filed with the FDA last month to start a clinical trial with CRISPR edited T cells for cancer (Link to paper), representing an interesting reprise of the T cell starting point for each of the three technology areas.

Putting these three cycles of technologies together (Figure C), we see the wave of stem cell gene therapy, CAR-T and gene editing moving through highs and lows over the past 25 years.  The curves intersect in 2015-2016 where the interest in the fields converge as stem cell gene therapy reached a plateau of productivity with solid clinical data in multiple diseases and one filed medicine, CAR-T cells reach an expectation peak on expanded clinical results and multiple partnerships, and gene editing emerges on the CRISPR/Cas9 expectations with a peak based on preclinical results, TALEN clinical results, biotech investments and public imagination.


A couple of final crystal ball observations to conclude:

  1. The clinical experiences from stem cell gene therapy and CAR-T fields would suggest that the early translational studies of gene editing approaches will be challenging and may lead to a dip in expectation. The capital raised by the early biotechs in the field, and their partnerships, will be useful for navigating through the next phase with further improvements and technological innovations.
  2. Cell therapy infrastructure will continue to be expensive and know-how with this modality are barriers to entry for many companies. More inter-company partnerships are likely to develop as companies consolidate their manufacturing cost base in tandem with new companies entering the field potentially with geographic, disease or technology partnering strategies. If late-stage assets are included, then these deals are likely to be large.
  3. The success of stem cell gene therapy is built on more than 50 years of transplant medicine. We know a lot about the biology of hematopoietic stem cells and more than 1 million patients have been transplanted globally. Many of the diseases targeted for stem cell gene therapy and gene editing medicines can be cured by transplants, when a matched donor can be found. Unfortunately, significant challenges remain in preparing patients for this procedure which has enabled the application of the patient’s own cells for gene therapy. New science will be needed to transform this field in the coming years.

With a switch from T cells to stem cells and a roller-coaster hype ride, the gene therapy field has delivered on its promise from over 25 years ago with a medicine that now offers a real hope for children with ADA-SCID.  At the heart of the journey to Strimvelis are patients and their families, starting with Ashanti DeSilva who was the first ADA-SCID patient to receive gene therapy with her own modified T cells. We owe a huge debt to the brave families who enrolled their children on clinical trials, together with the clinical giants who led this work and provided vital learnings for the adjacent fields for the future. The next chapters for CAR-T and gene editing will be compelling, especially if they are able to both seed new technology developments and bring curative medicines to patients.


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