After the Paper | Heart Stem Cell Therapeutics 8.0

We are living in an age of disruptive information technology, driven by a relentless series of iterative advances.  Blockbuster gives rise to Netflix. A cash-based society is replaced by cash-less apps. The local mall tries to meet the Amazon challenge.  And all of the above are accessed by your new iPhone 12.

And so it is with biotechnology. Never has this been clearer than in reviewing the sordid history of cell-based therapy for heart disease (Figure 1) (1- 9).

While initially couched as disruptive, many of the studies turned out to be false, ambiguous, and/or premature. Upon careful review, the field has gone through a sequential series of scientific mis-steps, that, in retrospect, primarily relate to basing the therapeutic payload on non-cardiogenic cells and failing to address the issues of optimizing cell delivery, survival, grafting, scalability, and safety.  A series of new technologies will be needed to reverse advanced heart failure, which remains a growing, world-wide unmet medical need. In short, it has been easier to rationalize than realize stem cell therapeutics. Nevertheless, as the old Dylan lyric goes, “the times they are a-changin’.“

 In our NBT perspective (1), we outlined a daunting series of scientific and technical hurdles that must be met to unlock the therapeutic potential of heart stem cell therapy (Table 1).  In the past 18 months, there have been dramatic scientific, medical, and financial advances which suggest that the field may be on the verge of an inflection point, driven by core advances in the biotechnology of human pluripotent stem cells. On the scientific level, general proof of concept that human embryonic stem (ES) cell derived cardiomyocytes can graft and reverse dysfunction in the heart post MI has been established (7).  These studies raise the query of how to tackle the scalability challenge, given the need for injecting billions of cells into the heart; most of which will not survive the initial implantation and do not migrate or expand past the initial injection site.  Problems of life-threatening arrhythmogenesis remain (10), as well as devising optimal approaches for percutaneous catheter-based delivery that meet strict safety and efficiency criteria.  Custom device technology is likely to intersect with stem cell therapeutics to address this critical barrier.  With regard to scalability, advances in 3D culture and-or robotics have allowed massive expansion of other differentiated cell types from human pluripotent stem cells (beta islet, dopaminergic, etc.) that are coming online.

 For the past 7 years, our labs at Karolinska Institutet (KI; Chien) and AstraZeneca (AZ; RFD) have been working on vascular regeneration by translating work initially done in mice (11) to large animals (12) and onward to First Time in Human (FTIH) studies, that were published in Nature Communications (13) just shortly before our NPG piece. At the time, our collective thinking already was beginning to turn to heart muscle cell regeneration, based on a long series of studies spanning 15 years based on the discovery of multipotent heart progenitors that build the heart in all mammalian species (Figure 2)(14-19).  Subsequently independent labs, most notably the Menasche lab have taken this further toward studies in primates (20) and a single case study in patients (21).  Right before our NBT perspective was published, we established a joint effort to unlock the therapeutic potential of human ventricular heart progenitors derived from human ES cells to reverse heart failure (22-23), based on work at KI that established their potential scalability and efficacy (9).  As the thinking goes, perhaps the heart progenitor would have inherent advantages over the fully differentiated cardiomyocyte in terms of generation time, ability to expand following in vivo grafting, viability, migration beyond the site of needle injection, and in integration to the native myocardium and maturing in a more normal manner without triggering ventricular tachycardia, a life threatening side effect found with all the studies employing differentiated human induced pluripotent stem cells (iPS) or ES derived cardiomyocytes.  Notably, in the setting of cell therapy for Parkinsons, the projected clinical cellular payload has been proposed to be dopaminergic progenitor cells, as it appears that they may have the most potential to reconnect to the native neural circuitry.  

 In addition to our own work, the field of cell based therapy, initially spurred by chimeric antigen receptor T (CAR T) cell therapy for cancer, is beginning to take hold for regenerative therapeutics in general.  Semma Therapeutics is merged with Vertex, and driving forward with beta islet cells for diabetes.  Bluerock has been acquired by Bayer and late stage planning of dopaminergic neuronal progenitors for Parkinsons.  Astellas is moving forward with human iPS derived retinal pigmental cells for eye diseases. A single case study suggests long term safety of autologous iPS derived cell based therapy for Parkinsons (24). Novo Nordisk A/S and Karolinska Institutet have entered into a collaboration to produce a cellular therapy, from human embryonic stem cells, for treating dry macular degeneration.  Newcos fostering larger scale production of ES or iPS derived differentiated cell types, including Vicardiomyocytes, have now found funding. GMP cell production facilities are sprouting up due to the documented efficacy of CAR T cell therapeutics for blood diseases, and a host of next generation technologies are moving forward to advance these to non-autologous iPS derived natural killer (NK) cells, as well as the development of adjunctive therapies that could extend efficacy to solid tumors.

 For the CVRM field, the future is likely to go beyond human ventricular progenitors (HVPs) to encompass other unmet clinical needs (25). Despite recent advances in reducing the morbidity and mortality of cardiovascular, renal and metabolic diseases such as the approvals of SGLT2 inhibitors, there is currently no therapy which stops disease progression. CVRM diseases are degenerative and the only curative option today is organ transplantation, an option for few patients due to the lack of donor organs. Recent advances in the science behind renal and liver regeneration are additional areas where cell therapy is likely to play a key role in the future.

 In the past 18 months since the publication of our NBT Perspectives (1) and the “About the Paper” follow-up (26), we have been able to progress the HVP project closer to IND and towards “first-in-human studies” (Table 1). Nevertheless, many challenges remain that will ultimately require a host of new discoveries, including tackling the issues of immunosuppression, graft rejection and graft-versus-host complications, limiting batch-to-batch variations in cell production, identification of graft allo-antigens and subsequent approaches to tolerization, generation of potential universal cell lines, development of surrogate indices of early efficacy and safety in Phase 1-2 studies, and optimizing the cost-of-goods to allow widespread access to the therapeutic worldwide.  Undoubtedly, by working together, the next generation of physicians-scientists-inventors-entrepreneurs, will be well-positioned to write a future NBT Perspectives on Heart Regeneration 9.0.

References

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