Academic-Industry Partnerships: Transparency, Potential Conflict of Interest and Communicating State-of-the-Art Technologies

Converting basic science discoveries into tangible diagnostic tools and therapies for human diseases is simultaneously valuable and daunting. Always looming in the background is the potential that translatable research knowledge may have commercial value in addition to its clinical and societal value. The researchers must determine what, if anything, should be done to ensure appropriate and fair retention of rights to their work and discoveries. In previous eras, when a scientist made a discovery in the laboratory that showed clinical utility, the potential for financial benefit was at best an indirect consideration. The most striking example may have been the transfer in 1923 of all commercial rights for insulin from the Canadian scientists who discovered it to their home university for a nominal $1 payment (1).

More recently in the United States (US), scientists’ motivation to hypothesize, experiment and discover opportunities to intervene on human disease was transformed in 1980 by passage of the Bayh-Dole Act (2). This watershed legislation irrevocably changed the pathway from research to commercialization (2). Previously, US grantee institutions assigned patents emanating from research activities to the federal government. After Bayh-Dole, academic and federally-funded institutions retained the ability to identify patentable discoveries from investigator-driven research and to forge ahead with patenting and development. This balanced the need to expeditiously bring a discovery into the clinical realm while concurrently ensuring that those who actually performed and supported the underlying basic science were fairly rewarded.

One outcome of the need to integrate competing academic and commercial interests was the birth of the “technology transfer office”, which has become a fixture in academic institutions in North America and worldwide (3). These offices support academic research scientists in negotiating a definitive path to license their discoveries to commercial interests - large or small - or even to participate in the launch of venture capital-funded start-up entities, in exchange for a share of equity (3). Funds arising from these new opportunities could be directed back to the institutions where they might help, at least partially, to fuel new research initiatives and also support the university infrastructure that enabled the foundational basic or pre-clinical research.

The links between academia and industry that were forged following Bayh-Dole have encouraged further creative opportunities to stimulate academic entrepreneurship, in the form of incubators, accelerators, science parks and venture capital funds, which in turn are further supported through institutional initiatives and investments (2). Hence, it was not surprising as time passed that academic investigators became more aware of – and even sought out – opportunities to identify purposeful and creative measures to accelerate the translation of their research towards the clinic.

A leading example of a burgeoning field whose lifeblood is academic-industry partnerships is that of therapeutic gene-targeting technologies. These include nucleotide base editing, gene therapy, RNA interference and antisense oligonucleotides, all of which are being designed, developed and tested in small animal models, non-human primates and, more recently, in humans (4). The rapid advancements utilizing these technological platforms hold great promise for the treatment of many chronic diseases such as familial hypercholesterolemia (FH), sickle cell disease, ß-thalassemia, T cell acute lymphoblastic leukemia, CD7⁺ acute myelogenous leukemia, glycogen storage disease 1a, Stargardt disease, α−1 antitrypsin disease, and transthyretin amyloidosis among many others (5,6). Through a range of gene-targeting approaches, both to modify expression of mRNA for either qualitatively abnormal or normal gene transcripts or efforts to outright permanently rewrite somatic genomic DNA promises to provide beneficial and durable treatments for potentially millions of patients globally (6).

The academic investigator, faced with unmet clinical needs and inadequate therapies for severe diseases, is increasingly claiming a more pro-active role in the design and delivery of such gene-targeting technologies, as well as in the vetting of the emerging results. As an example, in the current issue of Arteriosclerosis, Thrombosis and Vascular Biology, a commissioned review by John Kastelein and colleagues describes several state-of-the-art technologies to suppress production of proprotein convertase subtilisin kexin type 9 (PCSK9), which in turn reduces plasma levels of low-density lipoprotein (LDL) cholesterol to the benefit of patients with heterozygous familial hypercholesterolemia (FH) (7) but also potentially individuals at risk of atherosclerotic cardiovascular disease more broadly. Mechanism of action and treatment using both small interfering RNA and gene-targeting technologies, including CRISPR-Cas9-directed approaches, are described in the review from Kastelein and colleagues.

Our readers may ask “why is ATVB publishing this commissioned review?” The genesis of this article can be traced to an invitation to Dr. Kastelein, a pioneering distinguished academic researcher from the Netherlands to speak on this topic at a special ATVB sponsored symposium at the 2022 American Heart Association Scientific Sessions in Chicago. Dr. Kastelein kindly agreed and subsequently delivered a stellar lecture about novel targeted therapies primarily for FH patients. The resulting excitement prompted a second invitation from the senior editors to Dr. Kastelein to prepare a brief review for ATVB based on his presentation (7).

As is customary for such invited articles, Dr. Kastelein was encouraged to invite co-authors. To elevate the scientific stature and academic value of his manuscript, Dr. Kastelein invited scientists with direct first-hand experience, whom he knew could provide authoritative input on the rationale, development and implementation of these new therapeutic platforms.

As it turned out, some of co-authors were also employees of companies that are developing these technologies. Others served as paid consultants. These companies include Alnylam, which developed a short interfering RNA against PCSK9 that is now approved around the world (inclisiran) (8) and Verve Therapeutics, which initiated human trials of base-editing by CRISPR-Cas9 to knock out genomic PCSK9 (9) in hepatocytes of patients with severe FH. These co-authors provided essential text for their respective sections of the manuscript.

The first version of the manuscript was received at ATVB in December 2022 and underwent the usual anonymous peer review process. All three reviewers were enthusiastic about the scientific content and interpretation. However, one reviewer pointed out that two co-authors were academic scientists who were also employed by Verve and another was a long time employee at Alnylam. Quite apart from the quality of the manuscript, which this reviewer ranked highly, the appearance of conflict of interest entered into the review process as a new element of potential concern.

Although there is a detailed Conflict of Interest policy for the American Heart Association journals, the senior editors of ATVB - and editors of other American Heart Association journals - had no existing playbook of instructions or standard operating procedures to deal with this specific circumstance. Therefore, the ATVB editors sought advice from their trusted managing editorial team, from four senior editors at ATVB and finally from the American Heart Association (AHA) Science Publishing Committee. After a series of emails and zoom calls, all eventually agreed that: 1) the manuscript was of high quality that provided unique information, perspective and first-hand experience, and would certainly be of interest to ATVB readers; 2) the concern about the appearance of conflict of interest should be communicated to the authors; 3) the authors should be allowed to respond to these concerns; and 4) there should be full transparency on the relationship between portions of the text and intellectual property and commercial interests of employers of particular co-authors.

Upon learning of these concerns, Dr. Kastelein remarked that potential conflict of interests had not even crossed his mind as he was planning the article. He engaged the co-authors with the intention of enhancing the scientific content and authoritativeness of the review. All of them had been acquaintances over decades of academic collaborations and interactions at scientific sessions including AHA, International Atherosclerosis Society, Gordon, Deuel and Kern Conferences, etc. Dr. Kastelein described that he was thrilled when each of them accepted his invitation to help write the sections describing the respective methodologies that they were developing.

In addition to requiring thorough declarations of competing interests, the authors were asked, at the revision stage, to ensure mention of, as much as possible, of all entities known at present to be employing gene-based technologies to target PCSK9 for treatment of FH. The authors were also asked to review known adverse events ascribed to targeting PCSK9 in animals or in humans or to gene editing, in general.

In response, the revised manuscript clearly specified the ties to industry of the co-authors and the commercial interest in some of the products presented in detail, e.g. PCSK9 inhibition via the small interfering RNA (siRNA) inclisiran and the genomic base editing system VERVE-101. Transparent consideration of potential adverse events was also discussed in depth. We note that the revised manuscript balances the focus on these two products with additional text and a table that mentions other agents under development to target PCSK9 using platforms such as allele specific oligonucleotides, vaccines, adnectins and other siRNAs. In addition, there is a section on other approaches for genome editing, although here there seem to be fewer competitors and at less advanced stages of development (10).

Upon reflection, the ATVB editors have determined that readers will benefit from publication of these state-of-the-art approaches to gene-based technologies targeting PCSK9. Intervention during review enhanced transparency regarding authors’ competing interests and broadened the range of gene-based technologies discussed (7). Having gone through this experience, the editors believe that having more explicit guidance readily available will be helpful when future submitted manuscripts with potential conflicts of interest are identified. Other AHA family journals have responded editorially when comparable concerns arose about papers they published, e.g. editorial responsibility when an article described unregulated interventions (11).

We wonder if the sustained spark in creative and innovative means to propel new strategies, targets and therapeutic opportunities – and to fund and launch them – is but an intended consequence of efforts initiated more than 40 years ago, at least in the US, to enable investigators and institutions to execute their visions to reduce the burden of human disease. If so, then ATVB will be on-board as technologies advance to mitigate chronic diseases in our field, including those traceable to discrete genes and their downstream targets. We believe that it is our obligation to navigate the fine lines connecting investigator-initiated/company-enabled innovations with transparency regarding competing interests with an unbiased review of the overall target landscape, including the competitors and their platforms, as well as the safety margins. The editors enthusiastically accept this challenge to carefully consider such contributions in order to keep our readers informed as future opportunities emerge.