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Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop (2018)

Chapter: 5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships

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Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

5

Accelerating Research and Clinical Translation: Consortia and Public–Private Partnerships

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

Accelerating research on traversing the blood–brain barrier (BBB), and facilitating clinical translation of this promising science and these promising technologies, will require increasing collaboration across various stakeholder communities, including academia, industry, the private sector, and federal agencies, said Sarah Lisanby, director of the Division of Translational Research at the National Institute of Mental Health (NIMH). In a series of presentations, workshop participants representing an array of consortia and public–private partnerships (PPPs) established both by governmental and private agencies described how they have been instrumental in advancing research and development in other areas of neuroscience and suggested that their experiences could provide a roadmap for the BBB field.

CONSORTIA, FOUNDATIONS, AND PUBLIC–PRIVATE PARTNERSHIPS THAT SUPPORT ADVANCES IN SCIENTIFIC AND CLINICAL SCIENCE

Several collaborative efforts are under way to facilitate the development and clinical research of novel methods for delivery of therapeutics across the BBB. Ongoing projects in the United Stated and Europe provide lessons on what is needed to move the field forward and inform new funders who may provide novel approaches to catalyze research.

Innovative Medicines Initiative

The Innovative Medicines Initiative (IMI) is a European PPP of the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA).1 Stowasser said that between 2008 and 2024, IMI anticipates investing €5 billion (nearly $6 billion) to accelerate drug development in Europe. Half of this investment is coming from the European Commission, with the other half from the pharmaceutical industry in the form of people and expertise. Academic partners are selected by a neutral panel through a highly competitive process, he said, and they

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1 See http://www.imi.europa.eu/about-imi/history-imi-story-so-far (accessed January 24, 2018).

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

work alongside industry partners in precompetitive space with a requirement that decisions are reached through consensus from all partners. Stowasser noted that another factor that enables IMI to move projects forward is clear, up-front understanding of how intellectual property is managed: each owner or developer of intellectual property maintains ownership (or joint ownership if multiple developers are involved).

Among about 60 ongoing IMI projects, Stowasser said two are relevant to the BBB. COMPACT (Collaboration on the Optimization of Macromolecular Pharmaceutical Access to Cellular Targets) aims to understand the intracellular uptake of biologics. This project has yielded new formulations for noninvasive delivery of macromolecules, a better understanding of the function of different barriers, and potential novel targets, said Stowasser. A second upcoming project on the BBB aims to discover and characterize new targets and transport mechanisms for brain delivery of therapeutics to treat neurodegenerative and metabolic diseases.

PPPs such as the IMI approach provide benefits for all stakeholders, said Stowasser. Academic researchers join and shape a vibrant, productive environment and gain development expertise while translating basic research into benefits for patients; pharmaceutical companies address bottlenecks in drug discovery by sharing and pooling data, knowledge, skills, and risks; and small and medium-sized enterprises build partnerships that enable them to perfect and advance their innovations. Lack of reproducibility, a common problem in academic research, is addressed by validating results at multiple research centers, said Stowasser.

The BRAIN Initiative

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative was launched in 2013 by President Barack Obama as a partnership of federal and nonfederal agencies and organizations focused on mapping all the circuits in the brain. Today the BRAIN Initiative includes foundations, independent research institutes, major research universities, and industry partners, and it has been supported by more than $150 million for research.2

Edmund Talley said that the BRAIN Initiative interfaces with strategies for crossing the BBB because of their relevance to issues of accessing and understanding circuity activity and modulating circuits. For example, he noted that the neurovascular unit is a critical component that regulates

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2 See https://www.braininitiative.nih.gov (accessed January 24, 2018).

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

circuit activity (Ivanova et al., 2016). Talley said that the BRAIN Initiative exemplifies how the National Institutes of Health (NIH) can play an important role in establishing PPPs because of its access to the research community and understanding of where research is moving in the future. Moreover, NIH serves as a neutral third party, able to convene and liaise among academics and industry scientists. This has been particularly important in advancing research in the area of neuromodulation, he said, which, like the technologies discussed for traversing the BBB, requires the collaboration of multiple stakeholders from the pharmaceutical and device industries and thus has a complicated intellectual property and regulatory landscape. For example, the National Institute of Neurological Disorders and Stroke (NINDS) was interested in repurposing existing devices for new indications, and was able to convince companies that it was in their interest to share preexisting safety data on their devices with investigators funded by the BRAIN Initiative, and to put information about their devices on the BRAIN Initiative website. They also set up a template research agreement for companies to use as a starting point for negotiations over intellectual property, said Talley.

Wellcome

Private funders have also played important roles in supporting research. For example, Wellcome,3 which has an endowment of about $30 billion, invests approximately $1.2 billion per year to advance the development of technologies for treatment and diagnostics to improve human health, said Andrew Welchman, head of neuroscience and mental health at the trust. Their grant-funding portfolio includes about £500 million (about $650 million) for neuroscience and mental health. Only a small fraction of that has supported research on the BBB; however, Welchman suggested that there is an opportunity to increase funding in that space. He noted that there have been few grant applications pertaining to the BBB. In addition to providing individual fellowships and investigator awards, Wellcome supports interdisciplinary teams working at the interface of science, technology, and innovation, he said.

Wellcome funds internationally and works in partnership with other funders, both governmental and nongovernmental, said Welchman. It re-

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3 See https://wellcome.ac.uk (accessed January 24, 2018).

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

cently hosted a workshop on academic–industry partnerships, which focused on overcoming barriers to innovation, derisking investments, and leveraging the expertise in academia and industry.

Chan Zuckerberg Initiative

One of the newest philanthropic initiatives in the biomedical research space is the Chan Zuckerberg Initiative (CZI).4 Science is one of CZI’s three major areas of interest, along with education and policy, said Katja Brose, science program officer at CZI. Its efforts will be focused on basic biomedical science where more financial support, advocacy, and platform development are needed to break the bottlenecks that have slowed progress, she said.

A feature that sets CZI apart from other funders is its world-class technology engineering team. By assembling top engineers from areas outside of the scientific community who have experience managing and interpreting enormous quantities of disparate data, CZI hopes to leverage its expertise in partnership with scientists to advance the development of enabling tools and technologies that can drive innovation in biomedicine, said Brose. It has identified neurodegeneration and biological imaging and computation as two areas of particular interest. In the area of neurodegeneration, for example, it plans to bring together engineers, computer scientists, and cell biologists to explore mechanisms of neurodegeneration in novel ways, said Brose. One of its other early-stage efforts has been to join the Human Cell Atlas (HCA) Project consortium, which aims to use new technologies around single-cell sequencing, next-gene sequencing, imaging, and other technologies to develop a foundational atlas of every cell in the human body. CZI provides funding for several aspects of the project. It is collaborating with scientists and engineers at other research institutions to build a data coordination platform, and it is working with HCA scientists to develop new tools and technologies for the entire scientific community, said Brose.

Brose said that CZI is also committed to supporting the next generation of scientists by changing the culture and institutional context around rewards and incentives in academia, which will give young scientists the freedom to be innovative and open minded.

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4 See https://chanzuckerberg.com (accessed January 24, 2018).

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

XPRIZE Foundation

Grant Campany, a senior director at the XPRIZE Foundation,5 offered an alternative approach to problem solving, what the XPRIZE Foundation calls incentivized competition. The XPRIZE Foundation issues a challenge, defining very explicitly what it is looking for in terms of a solution, said Campany. It assembles an international team of key opinion leaders in the scientific community with specific types of expertise to evaluate submissions and the teams submitting them. The teams progress through several rounds of judging, with clear milestones that must be reached along the way, culminating in a large cash prize. For example, Campany recently ran a prize competition to develop a portable, wireless technology to monitor and diagnose health conditions and thus expand access to health care and better use limited health care resources. He said 300 teams from leading research institutions around the world vied for the prize, and after 4 years and extensive testing of prototypes, two teams were selected as winners, taking home several million dollars.

Campany said the prize approach helped accelerate the path to getting these devices commercialized. The advantages of this approach, he said, are that competitors are not restricted by current ways of approaching a problem, and doors are opened to collaboration. He added, however, that to be qualified as an XPRIZE, the end point must be well articulated, which can be challenging for basic science questions.

Kelsie Timbie of the Focused Ultrasound Foundation suggested a related funding model (without the aspect of a prize)6 that combines competition with collaboration by selecting a disease model and metrics and then inviting participants to test their particular therapeutic agent or treatment. She said that this approach accommodates different delivery mechanisms and multiple disease models for the same disease, and this approach has made it easier to decide how to move forward, particularly with early-stage research.

APPLYING THE CONSORTIA MODEL TO BBB RESEARCH

Following the session on consortia and PPPs, Sarah Lisanby asked if a consortium were to be established for the BBB, who its members would

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5 See https://www.xprize.org (accessed January 24, 2018).

6 See https://www.fusfoundation.org (accessed January 24, 2018).

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

be, what they would contribute, and what they would gain. Berislav Zlokovic advocated including people from multiple fields, such as vascular biologists, geneticists, scientists who focus on tau and amyloid beta, and clinical specialists.

Balancing Basic Science, Translational, and Clinical Research

Eric Schaeffer commented that the membership of a consortium would differ depending on the goal. For example, building basic science programs would require a longer timeline and different scientists, in comparison to a consortium aiming to move as rapidly as possible into therapeutic applications. Both are needed, he said. However, Danica Stanimirovic suggested that it may be a fallacy to divide basic science, applied science, and drug delivery into silos rather than thinking of them along a continuum. Consortia need to develop funding mechanisms that have a long-term perspective and enable development through that continuum, she said.

Consortia and other funders represented at the workshop ranged from those that are particularly adept at supporting foundational research, such the BRAIN Initiative and Wellcome, to those focusing on clinical outcomes, such as IMI. Welchman noted that while most of what Wellcome funds is in the basic sciences, there is also value in pursuing applications of those discoveries for the treatment of human diseases.

For riskier scientific endeavors, increased funding and education are needed, said Brose. But more importantly, the quality of the work must improve. For this, organizations such as CZI and XPRIZE may play a complementary role, funding projects submitted by individuals and groups that may be less likely to apply to more traditional funding organizations, said Lisanby. She noted that investing in basic science is an important part of the NIMH mission; Talley said the same is true at NINDS. In fact, he said that applications in basic neurobiology have a better chance of being funded, and at a higher pay line, than those submitted with a focus on a specific disease. Talley added that the potential for basic neuroscience is unprecedented. The ability to study single cells and to look at the diversity across the vasculature in the context of different disease states, as well as the potential for developing new models, have fueled tremendous excitement in the field, he said.

Chenghua Gu of Harvard Medical School, among others, advocated for an increased focus on basic science to expand the number of mechanisms that could be targeted. Stowasser said that in his opinion, the key is

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

to recognize the problem, bring together the right people, and be ambitious. Welchman agreed, adding that having good baselines across different experiments will encourage the emergence of innovation.

Training and Attracting Scientists to BBB Research

Thorne suggested that funders establish centers of excellence in BBB science, with programs that would support the training of BBB scientists and provide incentives for them to stay in the field. For example, he suggested a three-tiered system that could provide funding for graduate studies, after which successful trainees would have priority for postdoctoral fellowships. Those who stay in the BBB field for their postdoctoral fellowship could then compete preferentially for seed financing to set up a new lab. This would expand the field by producing a cohort of BBB scientists, and the effort could also build up critical infrastructure, he said. Brose, however, suggested that establishing a program on BBB science may be too narrow, shutting out scientists who could bring needed expertise, ideas, and tools to the field. She suggested that such a program could be built around the topic of neurodegeneration, with BBB a component of that.

To attract more young scientists to the field, Gu advocated increased visibility for the novel, exciting work being done in the field. Steven Hyman noted that glia and endothelial cells were not considered interesting until research by Ben Barres, professor of neurobiology at Stanford, showed that they were important players in neurodegenerative disease.

Robert Thorne agreed that researchers in this field occupy a unique interface. Even though there is an International Brain Barrier Society and a number of thriving research conferences, there are probably fewer than 2,000 scientists in the field, he said. Moreover, BBB research has been conducted in silos, added Brose. She argued for engaging other disciplines, such as cell biology and engineering, into the research enterprise. Thorne agreed that while the field is small, it is truly multidisciplinary, comprising physicists, modelers, immunologists, cell biologists, and neuroscientists, while straddling basic and applied science.

The nature of this multidisciplinary science surrounding the central nervous system (CNS) barriers field has probably posed a problem in identifying just which departments or schools would make the best home for highly qualified CNS barriers scientists. He also suggested that the diffuse nature of the field can make it less appealing for federal funding agencies because there are often not well-defined study sections with the right fit

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

and expertise to review grants that focus on CNS barriers work. Lisanby noted that small fields can benefit from cooperation and forming of consortia across groups.

Campany added another element to the equation: the importance of focusing attention on a problem and creating interest from a pool of talented individuals in outlying fields. Competition can encourage this, he said, bringing new insights and new ways of thinking into a problem. Not everyone agreed on the value of competitive models. William Potter suggested that competition gets in the way of progress and wastes resources. He supported international cooperative efforts as an alternative. Andrew Welchman elaborated on international collaborative awards, noting that teams funded by Wellcome bring together purely academic teams or teams of both academic and industry scientists. To secure funding from Wellcome, the principal investigator would have to be located in the United Kingdom, Ireland, or a lower- or middle-income country, he said. Coapplicants, however, can be located anywhere.

Additional Focus on Delivery and Regulatory Science

Thorne suggested that a roadblock to the treatment of brain disorders has been the pharmaceutical industry’s lack of appreciation for delivery science as opposed to drug development. Investments through consortia and PPPs could remedy this, he said. Regulatory science represents another research area that is underappreciated by the academic community, said Talley. The field could benefit from increased research in this area, he said, noting that NIH and NINDS would welcome investigator-initiated proposals in this area. He also noted that the BRAIN Initiative plans to fund studies to better understand the biophysics underlying invasive devices, which will have substantial regulatory implications. The IMI also holds a regulatory forum every year to identify topics that need to be addressed in regulatory science.

FINAL THOUGHTS

The purpose of this workshop, according to Steven Hyman, was to bring together industry, government, foundations, patient groups, and academics to discuss important issues, gaps, and bottlenecks in the neurosciences, especially those related to the BBB, and to share ideas for possible

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×

solutions to outstanding questions. Indeed, the workshop discussions identified many unanswered questions.

William Potter suggested that advancing understanding of the BBB could be achieved through a systematic evaluation and prioritization of tools. For example, he suggested that the technology already exists with positron emission topography imaging and radiolabeled ligands to quantify a biologic agent as it enters the brain, yet these tools are not being used for this purpose. As a result, even after investments of billions of dollars, studies conclude with no interpretable data about dosing, he said.

Welchman compared the problems discussed at the workshop to the moon shot. The technology involved in going to the moon required bringing many elements together. Here, many tools have been discussed; now the challenge is to integrate them, he said.

Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
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Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 32
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 33
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 34
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 35
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 36
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 37
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 38
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 39
Suggested Citation:"5 Accelerating Research and Clinical Translation: Consortia and PublicPrivate Partnerships." National Academies of Sciences, Engineering, and Medicine. 2018. Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25044.
×
Page 40
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Despite substantial advances in developing treatments for the serious illnesses that affect people worldwide, there remains a tremendous unmet need in the treatment of complex neurologic diseases, including neuropsychiatric and neurodegenerative disorders. Chief among the challenges that have hindered the development of therapeutics for central nervous system (CNS) disorders is the blood–brain barrier (BBB). The Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine convened a workshop to explore the challenges associated with the BBB that have thus far stymied development of CNS drugs, examine new technologies that could address these challenges, and highlight potential opportunities for moving the field forward. This publication summarizes the presentations and discussions from the workshop.

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