Unlock the White House Watch newsletter for free
Your guide to what Trump’s second term means for Washington, business and the world
Donald Trump has threatened to launch fresh strikes against Iran if it is found to be rebuilding its nuclear…
UCLA Health clinicians and scientists are working to change the trajectory of osteoarthritis (OA) treatment from a prevention and treatment-of-symptoms model to regeneration of the entire joint. It’s part of a multi-institutional “moonshot” effort aimed at developing a groundbreaking treatment that is accessible, affordable and available in the shortest possible timeframe.
Currently, there is no cure for OA, a degenerative joint disease affecting 32.5 million people in the U.S. It causes pain, immobility, disability, and many downstream health and financial burdens. Additionally, OA exacts a national financial weight approximated at $136 billion annually.
Such a massive unmet health need requires an equally mighty effort to quell it. Enter the Advanced Research Projects Agency for Health (ARPA-H) Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO) program. Under this program, UCLA in collaboration with Duke University and Boston Children’s hospital was awarded up to $33 million to complete a project seeking dramatic changes in OA care.
“The funding provided by the NITRO program allows us to promote a novel concept,” explains clinician-scientist Thomas Kremen, MD, orthopedic surgeon and faculty member at the David Geffen School of Medicine at UCLA. “Project criteria require the development of therapy that regenerates bone and cartilage and targets joint tissues through a once-yearly injectable product. The goal is to go from concept to completion of an FDA phase 1 clinical trial within five years. In medicine, that’s the speed of light.”
The UCLA team considers all components of the joint holistically, as a single organ. The hope is to identify biologics that heal and regenerate joints to the point of possibly supplanting joint replacements.
For developmental biologist Karen Lyons, PhD, professor and vice chair of the research team, this project is personal.
“I have osteoarthritis, so I’m extremely motivated in translational research,” she says. “This ARPA-H-funded UCLA project has shifted my focus into finding an economically and clinically practical solution. We want something that anyone — a millionaire or an average Joe — can access.”
Dr. Lyons, whose lab studies signaling pathways causing cartilage to develop in utero, says UCLA Health is ideally positioned to carry out the level of research required by this ARPA-H-funded UCLA project. Because UCLA’s medical school and hospital are in close proximity to the basic science labs, “… we have cross-fertilization of ideas. In fact, Dr. Kremen and I share lab space. That’s unique,” she says.
Additionally, because UCLA Health is in the second largest city in the U.S. with one of the most diverse populations, it has “… the clinical infrastructure and geographic footprint to engage with many OA patients,” says Dr. Kremen.
For these reasons, UCLA Health will lead the clinical trial resulting from current research as early as 2027.
Participation in the NITRO program aligns with UCLA Health’s development of a longevity and anti-aging program, in part because OA is considered a disease of aging. However, ongoing research by Dr. Kremen underscores the point that increasing risk for OA may be established earlier in life. His lab is conducting a clinical trial to evaluate the use of a drug, anakinra, in people suffering a torn anterior cruciate ligament (ACL).
“We once thought ACL reconstruction would make the knee more stable and help prevent arthritis. But that’s not the case,” says Dr. Kremen. “It doesn’t prevent downstream OA from happening 10-20 years later.”
Dr. Kremen and team have tracked biomarkers occurring when an ACL is torn and have found pro-inflammatory molecules that can be targeted with anakinra, originally developed for rheumatoid arthritis.
“The theory is if we treat people early after an ACL tear and introduce a corrective molecule while the pro-inflammatory biomarker storm is going on, we can redirect those biomarkers and prevent OA down the line,” he explains.
This intervention following acute ACL injury takes advantage of a cartilage-sensitive MRI that can detect an abnormal signature on the cartilage. UCLA Health is among just a few institutions in the country that have this technology. Dr. Lyons says because Dr. Kremen has experience with clinical trials in the OA space, he brings real-life experience to the trial phase of NITRO, giving UCLA Health a strong advantage moving forward.
In addition to medical research funding, this ARPA-H-funded UCLA project supports translational aspects of the undertaking, such as navigating the Food and Drug Administration process, commercializing a product when successfully identified, scaling up production and making it equitably available to the masses.
The entire project has delivered a unique opportunity to those participating.
“In my entire career, I might treat 20,000 patients and have an impact on their lives. But if we can develop a viable therapy through NITRO, it has the potential to impact millions of people — the opportunity of a lifetime,” says Dr. Kremen.
Dr. Lyons adds that NITRO allows the research team to advance ideas that might never have a chance to be evaluated otherwise.
“There are very few funding opportunities that cater to this kind of project,” she says. “If you ever find one, take it.”
Clearly, the project criteria are very challenging. “But with commitment from many talented people and resources we’ve been provided, we can push the chances for success to be in our favor,” says Dr. Kremen. “People throw around the term ‘moonshot.’ But even if we fall short of the moon, we might get a new therapy that works on Earth. We can make a difference, and in our lifetime.”
Rodrigues, J. C., Haas, M. & Reich, H. N. IgA nephropathy. Clin. J. Am. Soc. Nephrol. 12(4), 677–86 (2017).
Tomino, Y. Predictors of prognosis in IgA nephropathy. Kaohsiung J. Med Sci. 28(10), 517–20 (2012).
Joo, Y. S. et al. External validation of the international prediction tool in Korean patients with immunoglobulin a nephropathy. Kidney Res. Clin. Pract. 41(5), 556–66 (2022).
Yao, X. et al. MicroRNAs in IgA nephropathy. Ren Fail. 43(1), 1298–310 (2021).
Zhang, Y., Yang, H., Jiang, M. & Nie, X. Exploring the pathogenesis and treatment of IgA nephropathy based on epigenetics. Epigenomics. 15(19), 1017–26 (2023).
Shema, E., Bernstein, B. E. & Buenrostro, J. D. Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution. Nat. Genet. 51(1), 19–25 (2019).
Spitz, F. & Furlong, E. E. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13(9), 613–26 (2012).
Ahmed, N. et al. Multi-omic analysis of longitudinal acute myeloid leukemia patient samples reveals potential prognostic markers linked to disease progression. Front. Genet. 15, 1442539 (2024).
Araki, Y., Fann, M., Wersto, R. & Weng, N. P. Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J. Immunol. 180(12), 8102–8 (2008).
Ma, S. et al. Chromatin potential identified by shared single-cell profiling of RNA and chromatin. Cell. 183(4), 1103–16 (2020).
Xie, S. et al. T cell responses in immune-mediated IgA nephropathy. J. Leukoc. Biol. 116(3), 523–35 (2024).
Ruszkowski, J. et al. T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. Clin. Exp. Nephrol. 23(3), 291–303 (2019).
Pei, G. et al. Renal interstitial infiltration and tertiary lymphoid organ neogenesis in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 9(2), 255–64 (2014).
Zheng, Y. et al. Single-cell transcriptomics reveal immune mechanisms of the onset and progression of IgA nephropathy. Cell Rep. 33(12), 108525 (2020).
Corces, M. R. et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat. Methods. 14(10), 959–62 (2017).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods. 9(4), 357–9 (2012).
Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 26(6), 841–2 (2010).
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9(9), R137 (2008).
Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 489(7414), 57–74 (2012).
Shin, H. M. et al. Chromatin accessibility of circulating CD8(+) T cells predicts treatment response to PD-1 blockade in patients with gastric cancer. Nat. Commun. 12(1), 975 (2021).
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 26(1), 139–40 (2010).
Budczies, J. et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One. 7(12), e51862 (2012).
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 38(4), 576–89 (2010).
Ivanek OBaR. seqLogo: Sequence logos for DNA sequence alignments. (2023).
Kramer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 30(4), 523–30 (2014).
Yi, M., Nissley, D. V., McCormick, F. & Stephens, R. M. ssGSEA score-based Ras dependency indexes derived from gene expression data reveal potential Ras addiction mechanisms with possible clinical implications. Sci. Rep. 10(1), 10258 (2020).
Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192(5), 2143–55 (2014).
Mizutani, S. et al. Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis. Br. J. Haematol. 170(6), 859–73 (2015).
Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity. 37(6), 1130–44 (2012).
Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 338(6111), 1220–5 (2012).
Man, K. et al. Transcription factor IRF4 promotes CD8(+) T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity. 47(6), 1129–41 (2017).
Chandele, A. et al. Formation of IL-7Ralphahigh and IL-7Ralphalow CD8 T cells during infection is regulated by the opposing functions of GABPalpha and Gfi-1. J. Immunol. 180(8), 5309–19 (2008).
Simundic, A.-M. Diagnostic accuracy—part 1: basic concepts: sensitivity and specificity, ROC analysis STARD statement. Point Care. 11(1), 6–8 (2012).
Deng, Q. et al. The emerging epigenetic role of CD8+T cells in autoimmune diseases: a systematic review. Front. Immunol. 10, 856 (2019).
Uchimura, K. et al. The effects of CD40- and interleukin (IL-4)-activated CD23+ cells on the production of IL-10 by mononuclear cells in Graves’ disease: the role of CD8+ cells. Clin. Exp. Immunol. 128(2), 308–12 (2002).
Xing, L. et al. CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol. Med. Rep. 10(3), 1252–8 (2014).
Blanco, P. et al. Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 52(1), 201–11 (2005).
Jung, S. & Baek, J. H. The potential of T cell factor 1 in sustaining CD8(+) T lymphocyte-directed anti-tumor immunity. Cancers (Basel). 13(3), 515 (2021).
Grenningloh, R. et al. Ets-1 maintains IL-7 receptor expression in peripheral T cells. J. Immunol. 186(2), 969–76 (2011).
Grambling, La. – The Centenary men’s basketball team returns to the court on Tuesday as the Gents will face the Grambling State University Tigers in an exhibition contest set for NOON at Willis Reed Court at the…
SAN ANTONIO – Cured will serve their last meal after over a decade in the heart of Pearl, a manager of the San Antonio mainstay told KSAT.
The six-time James Beard Award…