Michigan-Pittsburgh-Wyss Resource Center: Driving New Innovations in Regenerative Medicine

Translation of Regenerative Medicine Therapies: Extraordinary Potential and Unique Challenges

Regenerative Medicine (RM) is an exciting and relatively new biomedical discipline that seeks to establish methods of repairing or replacing human tissue damaged by injury or disease. This research is multi-disciplinary in nature, and is driven by innovations in fields such as tissue engineering (TE), stem cell biology, materials science, and molecular biology.¹ As tissue and organ damage is a broad clinical problem caused by a countless number of medical threats, the development of commercially and clinically viable RM products has the potential to change virtually every field of medicine.

However, nearly two decades of extensive research in TE/RM have yielded only a handful of FDA-approved clinical therapies.¹ Though much of the lag in progress may be attributed to the complexity of the biologic and engineering problems being addressed, several other barriers to clinical progress have been identified:^2,3

• TE/RM technologies often straddle the line between designation as biologics, drugs, and medical devices, each of which have different regulatory processes for investigators to navigate during development.
• Production of these technologies, especially those combining cell-based products with biological scaffolding, requires the coordination of several manufacturing and Quality Control pipelines.
• National Institute of Dental and Craniofacial Research (NIDCR)-identified need for clinicians to articulate areas of clinical needs and to establish product design criteria.
• NIDCR-identified need for consideration of intellectual property (IP) protection and commercialization plans during translational research.

Academic researchers are well-equipped to address the key scientific questions and theory behind the therapies they are developing, but often lack the clinical and commercial translation expertise to understand how regulatory, manufacturing, and market forces may impact the design and development of their medical products. These concerns are often only addressed later in the preclinical development pipeline, which may significantly slow or halt progress in the clinical translation of these potential therapies. Therefore, success in clinical translation of novel TE/RM therapies is dependent upon the early consideration of all of the above factors.⁴ As a result, the NIDCR of the National Institutes of Health (NIH), and other organizations are beginning to incorporate these translational considerations into current grant structures.

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Accelerating Therapies for Dental, Oral, and Craniofacial Tissue Injury

The National Institute of Dental and Craniofacial Research (NIDCR) of the NIH is interested in boosting the development of regenerative therapies addressing damaged dental, oral, and craniofacial (DOC) tissues. Despite a clear clinical need for DOC-related regenerative medicine therapies, there has been little progress in these technologies in recent years, and limited investment into this field by the pharmaceutical and biotechnology industries. As a result, in 2017 the NIDCR created the Dental, Oral and Craniofacial Tissue Regeneration Consortium (DOCTRC), which aims to accelerate the translation of preclinical regenerative therapies for the field.² The mission of DOCTRC is to provide academic and small business translational research groups with financial and advisory resources from an interdisciplinary network of clinical, engineering, regulatory, and commercialization experts to accelerate development of their DOC therapies.

This consortium, the lifeblood of which is a three-year $24 million federal award, has created two DOC regenerative resource centers within the United States.² One of these centers is the Michigan-Pittsburgh-Wyss Regenerative Medicine (MPWRM) Resource Center, which is led by investigators at the forefront of regenerative medicine and craniofacial/dental research across the University of Michigan, the University of Pittsburgh, and the Wyss Institute of Harvard University.

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MPWRM Resource Center Structure and Progress

Each academic institution participating within the MPWRM Resource Center offers unique and complementary strengths to DOCTRC. The University of Michigan boasts a top 5 ranked dental school, is a leader in periodontal research, and offers extensive experience in the implementation of clinical trials and development of clinical products. The University of Pittsburgh contains a vast pre-clinical research operation for TE/RM research through its McGowan Institute for Regenerative Medicine and the Center for Craniofacial Regeneration housed within the University of Pittsburgh School of Dental Medicine. The involvement of these centers provides the use of disease-relevant large animal models and offers scientific, regulatory, and business expertise that pairs well with Michigan’s clinical background. Finally, the impressive bioengineering resources of the Wyss Institute of Harvard University will aid research teams in refining manufacturing protocols and developing prototypes, helping to create cost-effective and viable clinical products. sciVelo of the University of Pittsburgh leads the construction of commercial translation critical paths of each project, and the industrial partners program that strategically links university-based projects with industry.

With the structure and roles of institutions and leaders within DOCTRC clearly defined, most of the current effort involves supporting the research of promising groups within the Resource Center’s Interdisciplinary Translational Project (ITP) Program. Currently, there are 19 funded projects supported by the consortium, which are developing various medical products (biologic, device, cellular, and therapeutic) targeted at a wide array of DOC-related tissues. In order to receive up to $150,000 in research funding through the ITP, groups had to navigate two rounds of proposal submission and revision by DOCTRC. Only projects that could demonstrate validation in vivo and in vitro were considered for funding, as DOCTRC aims to move potential therapies towards clinical trials and submission of Investigational New Drug and Device applications within 6-8 years.⁵

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Incorporating Commercial Translation Perspectives into Pre-Clinical Research

Developing viable clinical products requires understanding the biomedical market surrounding that product, developing a comprehensive strategy for the filing of viable patents, and compelling market translation to attract attention from investors. Although the DOCTRC website contains a list of commercialization-focused training materials for investigators, the vital commercialization work of the consortium is being performed by two groups: The Avenues Company in Flagstaff, Arizona, and sciVelo at the University of Pittsburgh (now part of the Innovation Institute). The Avenues Company, a biotech marketing group with an extensive background specifically in DOC-targeted regenerative products, is providing necessary market analyses to determine if there is an unmet market need for potential products and how those products can be best positioned for clinical adoption. Regardless of scientific merit, therapeutic products have poor potential for success if they lack a financial niche to address, so an early consideration of market needs prevents the acceleration of commercial failures.

sciVelo has been recruited to both address the translational science strategy of these technologies, and to ensure that they are effectively translated and marketed to interested investors, incumbent companies, or licensed spin-out companies. According to Dr. Andrew Brown, the Assistant Director of Commercial Translation Programs at sciVelo, this involves the creation of a commercial translation roadmap for every funded project. These roadmaps help investigators understand what they should be focusing on during both preclinical research stages, and subsequent commercialization stages leading to marketed products. Dr. Brown thinks sciVelo’s role within DOCTRC has developed over time as each technology advances closer to clinical development.

Dr. Brown is proud that sciVelo and the Avenues company have helped investigators appreciate and implement commercial translation considerations into all decisions related to the development of these products within the host universities.

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Resource Center Highlight:

Controlled Released System for Immunoregulation and Treatment of Periodontal Disease

Dr. Steven Little, Chairman of the Department of Chemical and Petroleum Engineering at the University of Pittsburgh, leads one of six DOCTRC-funded projects within Pittsburgh. His technology seeks to address an oral health problem that impacts nearly 46% of American adults today: periodontitis.⁶

Patients with severe cases of periodontitis experience extensive degradation of gum tissue and bone, which is caused by the body’s potent inflammatory response against resident bacteria. Particularly, the 8.9% of periodontitis patients with the most severe form of the disease respond poorly to traditional treatment. Current therapies for periodontitis often aim to remove oral bacteria through antibiotics, which has the unfortunate consequence of contributing to the rise of antibiotic-resistant bacteria.⁶

However, Dr. Little’s novel therapy is a promising and antibiotic-free alternative, and targets the body’s uncontrolled immune response to bacteria rather than the bacteria themselves. His team has developed a specialized therapeutic polymer, which can be placed directly into pockets of damaged gum tissue. This polymer slowly releases a protein that attracts a specific population of white blood cells to the damaged tissue. These white blood cells can calm inflammation and promote tissue regeneration. This technology has already been shown to reverse periodontal disease-associated damage in animal models, and Dr. Little is very enthusiastic about the potential of his treatment:⁷

Dr. Little says he appreciates that DOCTRC is able to support the pre-clinical development of his research, suggesting that it has “given us life to explore studies which de-risk the technology”. He lamented that since most grant funding agencies are focused on funding new ideas rather than the translation of existing ideas, it can be difficult to get therapies moving toward clinical trials and investment without the support of structures like the Resource Center.

Dr. Little also commented on his interactions with experts connected through DOCTRC. “The knowledge base and technical expertise that consortium provides is quite formidable,” said Little. “I’m not sure if there is another network of experts like this one”.

As Dr. Little had already organized a number of clinical and regulatory analyses prior to joining DOCTRC. A great deal of his communication with the consortium has focused on commercialization and marketing concerns.

Dr. Little has no intention of failing, and that drive may someday benefit the millions of Americans currently diagnosed with severe periodontitis.

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Resource Center Highlight:

AxoMax: A Novel Conduit for Long-Gap Nerve Repair

Dr. Kacey Marra, Professor and Vice-Chair of Research for the Department of Plastic Surgery, is another University of Pittsburgh researcher with a promising DOCTRC-funded technology. Although an education within the Steel City has shaped much of Dr. Marra’s career, an early inspiration for her research was a chance encounter with the Man of Steel, Christopher Reeve.

A few years into her postdoctoral career, Dr. Marra found herself at a tissue engineering conference in Pittsburgh, which included a dinner attended by the late “Superman” actor Christopher Reeve. Reeve, a paraplegic and vocal advocate for spinal cord injury research, gave a speech at the dinner that resonated deeply with Marra:

Dr. Marra was able to quickly apply her expertise in biomaterials to the sphere of nerve regeneration, and in several years created a novel technology that effectively repairs peripheral nerve injuries. This technology, called AxoMax, has the potential to treat facial and tissue paralysis caused by nerve injury, which would dramatically promote the quality of life for individuals afflicted with those injuries. AxoMax acts as a physical scaffold for injured nerves to regenerate, and secretes growth factors that help promote nerve growth. Not only is AxoMax able to repair large nerve injuries that current FDA-approved strategies cannot address, in animal studies it showed a marked improvement in return to tissue function compared with the current standard of care.⁸

Dr. Marra said it was after this essential animal model validation that she decided to push the lab’s translational efforts, and she applied for DOCTRC funding to help move AxoMax towards clinical trials. Dr. Marra cites her interactions with regulatory and marketing experts within DOCTRC as being particularly invaluable.

She admits she has little familiarity with the FDA approval process, and appreciates that DOCTRC has provided Kay Fuller (President of Medical Device Regulatory Solutions) as a regulatory consultant to help navigate this daunting process. Dr. Marra also expresses gratitude towards DOCTRC marketing team, who have helped to pen a detailed marketing report that serves as a critical resource during meetings with potential investors.

With the strength of her expertise, the dedication of her team, and strategic help from DOCTRC, Dr. Marra is confident she can someday get AxoMax into clinics.

Citations

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Author: Ryan Staudt



Photographers: Ryan Staudt and Ceren Tuzmen, PhD

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