Stephen A. Adam, Ph.D., Associate Professor, Cell and Developmental Biology, Feinberg School of Medicine Northwestern University

Dr. Adam’s background includes extensive work on cellular mechanisms that establish and maintain cellular compartments and transport, which supports his understanding of vimentin in these processes. This work began when he was a postdoc with Larry Gerace at Johns Hopkins and then continued at Scripps, where he was a Damon Runyon/Walter Winchell Fellow. Later, he transitioned to studying the assembly and biochemical roles of intermediate filament proteins, in particular the nuclear Lamins and cytoplasmic vimentin, their post-translational modifications and effects on assembly, structure, and interactions with other factors in cells. He uses mammalian cell models to study transport within the cell.

As part of the Goldman group, Dr. Adam is widely informed on the history of the study of vimentin filaments, behavior, manipulations, disease correlations, and the rationale for safety for a drug that targets vimentin.

He has interacted with Aluda for 3 years, offering many insights on the nature of conformational changes, the allosteric nature of vimentins interacting proteins, and the long-term safe human use of the primary vimentin degrading tool compound in humans (WFA) in an herbal supplement.

Dr. Adam produced the second major vimentin Review paper Roles of vimentin in health and Disease (PMID: 35487686, Goldman), which summarized all literature on KO models, proving vimentin’s wide roles but mild phenotypes for those roles when absent. This was key to evolving the refined and current view in the field that vimentin regulates the adaptability or change of many cellular processes, but the role is not significant enough in normal conditions (both balanced and adapting cell process) to create an adverse reaction if absent. These facts of vimentin’s native biology are the most critical foundation to understanding how Aluda’s modulation drug action can be unable to interrupt or alter normal biology to create detriment or harm, and in parallel can achieve important efficacy by modulating vimentin’s role in driving those processes to overstimulation and maladaptation.

Michael Dustin, Ph.D., Director of Research, Kennedy Institute at Oxford University

Prof. Dustin has a B.A. in Biology from Boston University (1984) and a Ph.D. in Cell and Developmental Biology from Harvard University (1990). He studied glucose transport in red blood cells for his undergraduate thesis with Scott W. Peterson. He studied biochemistry and regulation of lymphocyte adhesion molecules during his PhD with Timothy A. Springer. He completed post-doctoral training with Stuart Kornfeld on lysosome structure and function at Washington University School of Medicine (1993).

Dr. Dustin led his own group at the Department of Pathology at Washington University School of Medicine under Steve Teitelbaum and Emil Unanue from 1993 to 2000. While at Wash U, he led a collaborative group in discovering requirements for the T cell immunological synapse with Andrey Shaw, Paul Allen, Mark Davis (Stanford) and Emil Unanue. He moved his lab to the Skirball Institute of Biomolecular Medicine at New York University School of Medicine in 2001. Continuation of work on the immunological synapse led to a basic description of the supramolecular assemblies that make up the mature immunological synapse. Specialized functions of the immunological synapse in cytotoxic T cells and regulatory T cells were also explored.

He was director of the NIH-funded Nanomedicine Center for Mechanobiology from 2009-2014. To further advance studies on the immunological synapse and translation to treatment of human diseases he moved to the Kennedy Institute of Rheumatology at the University of Oxford in 2013 supported by a Principal Research Fellowship from the Wellcome Trust.

Dr Dustin recognized the importance of a specific vimentin targeting molecule for further study of immune control through Tregs and Dr Compeer’s exploratory research with Aluda compound since 2020 has significantly expanded the proof of drug action in Tregs of different kinds. An expansion on the 2018 paper, with higher visibility, is planned that will correctly summarize the field of Treg manipulating approaches and the advantages of using vimentin. Drs. Dustin and Dr. Compeer have multiple grant applications underway to enable further research using Aluda drug, and we continue to refine collaboration concepts to provide compelling research evidence to support Aluda’s existing in vivo data sets in IBD, IPF, MS, RA, T1D, and beyond which showed their highest statistical significance in the most severe disease models, reflecting the potency of drug action to restore effective Treg functionality in diseases where that is a central deficit.

Annica Gad, Ph.D., Principal Researcher, Associate Professor, Karolinska Institutet

Dr Gad had a long tenure at the University of Sheffield where she pioneered the understanding of vimentin which she continues and expands at Karolinska, where she is leading a larger research consortium on filaments and cancer.

Over course of her career, Dr. Gad has had extensive conversations with the author of the seminal 1994 paper containing the initial Vimentin KO modeling that found no phenotype when it was absent (PMID: 7954832) . It was an extremely thorough examination, dissecting KO mice, KO rats, and their KO progeny, confirming that none displayed any abnormal phenotypes in the absence of vimentin.

This finding was completely unexpected and in sharp contrast to all previous intermediate filaments that had been characterized by KO, so it kicked off scientific debate and controversy that lasted for decades. How could such an abundant protein as Vimentin not create a deficit if absent? Dr. Gad has followed the controversy and counterpoints since an early date and was central in its resolution. She was the first to point out that all later papers that claimed to find phenotypes had needed to employ abnormal conditions or pressures to elicit those phenotypes.

This critical observation led to confirming vimentin’s conserved role is outside normal conditions. It is an expansive scaffold facility for cell processes to adapt their rate in response to a variable environment and enable resilience and change to maintain health. In disease, vimentin has the same role but in the presence of escalating signals of any kind in its interactome now creates the potential to expand the small changes of health it is conserved for into overstimulated or maladapted cell processes that produce pathology.

Dr Gad has multiple ongoing publications on her vimentin work and is an active member of the international filament biology community enabling Aluda conversations and collaborations. She continues to clarify the understanding of long-standing oncology research showing vimentin’s heightened presence in the epithelial-to-mesenchymal transition and how it complements the central mechanism of action for this drug in reducing the vimentin-enabled overstimulations in cancer that arise from heightened communication by exosomes. The problematic and unsolved role of upregulated exosome release is an extremely active field with wide proof that it could be a new intervention point for blocking how the tumor microenvironment is created and sustained, how metastases are primed, and how systemic metabolic dysregulation occurs, led by MD researchers at UPenn (W. Guo), Cedars Sinai (P. Noble), MD Anderson (R. Kalluri), MSK (D. Lyden), and UCSF (R. Blelloch) to name a few. We anticipate Dr Gad’s participation in future research with those entities that will expand on Aluda’s exploratory work (Aluda paper PMCID: PMC8297618) and may enable clinical study in this area as follow on indications.

Teja Kulkarni, MD, U Alabama Birmingham Medical School, Head of ILD unit

Dr. Kulkarni received her medical training and internship at Bangalore Medical College and Research Institute followed by a Masters in Public Health at Harvard T.H. Chan School of Public Health. She completed a residency in Internal Medicine at Wayne State University 2013 and a clinical and research fellowship at UAB in 2016, after which she was appointed as faculty for the Division of Pulmonary, Allergy and Critical Care Medicine and subsequently Director of Interstitial Lung Disease Program. She is on numerous committees including the steering committee of the ILD network at American College of Chest Physicians and has extensive experience as principal and co-investigator on clinical trials in IPF, ILD and other indications. Her research focuses on developing imaging biomarkers to predict and assess response.

Dr Kulkarni has closely reviewed Aluda’s fibrosis data across lung and liver and recognizes the high priority of clinical testing for this a vimentin-targeting drug given UAB’s role in establishing its importance. Being a biomarker expert, Dr. Kulkarni was particularly aware of the challenge Aluda faced of explaining a target that does not change quantity or level in disease. Her extensive trial and clinical experience with single-pathway target drugs provides her with first-hand knowledge of both an evasive biology that has escaped many pathway targets and a patient population unable to tolerate. Over multiple years, Dr. Kulkarni reviewed Aluda efficacy data closely, seeing its highly significant ameliorations of the multiple disease features UAB had shown central to disease. By having an action only on elevated disease signals, the UAB group recognized that Aluda’s drug creates the potential to ameliorate these component features of IPF as they occur, when they occur, tracking their shifting and evasive nature. This holds potential as an important breakthrough for patients non-responsive (or intolerant to) existing mechanisms. Dr. Kulkarni contributed to developing clinical trial designs with rapid readouts and greatest enrollment potential and will participate in trial leadership at the appropriate time.