[Mar. 5, 2023: Graciela Gutierrez, Baylor College of Medicine]
For chronic conditions such as rheumatoid arthritis, treatment often involves lifelong injections. (CREDIT: Creative Commons)
For chronic conditions such as rheumatoid arthritis, treatment often involves lifelong injections. Fear of needles, injection-associated infections, and pain are responsible for dose skipping among patients, encouraging the development of new delivery strategies that combine efficacy with limited side effects to adequately treat patients.
Researchers from Baylor College of Medicine and collaborating institutions have explored a better way to deliver drugs that don’t require injections, but could be as easy as swallowing a pill. The study appears in the Proceedings of the National Academy of Sciences.
“People don’t like having injections for the rest of their lives,” said co-corresponding author Dr. Christine Beeton, professor of integrative physiology at Baylor. “In current work, we have explored the possibility of using the probiotic bacterium Lactobacillus reuteri as a novel oral drug delivery platform to treat rheumatoid arthritis in an animal model.”
Previous work from the Beeton lab had shown that a peptide, or short protein, derived from sea anemone toxin safely and effectively reduces disease severity in rat models of rheumatoid arthritis and patients with rheumatoid arthritis. plaque psoriasis. “However, peptide treatment requires repeated injections, which reduces patient compliance, and direct oral administration of the peptide has low efficacy,” Beeton said.
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Beeton partnered with Dr. Robert A. Britton, professor of molecular virology and microbiology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. The Britton Lab has developed the tools and expertise to genetically modify probiotic bacteria to produce and release compounds. In the current study, the team bioengineered the probiotic L. reuteri to secrete the peptide ShK-235 derived from sea anemone toxin.
They chose L. reuteri because these bacteria are native to human and animal guts. It is one of the groups of lactic acid bacteria that has long been used as a cell factory in the food industry and recognized as safe by the United States Food and Drug Administration. L. reuteri has an excellent safety profile in infants, children, adults and even in an immunocompromised population.
“The results are encouraging,” Beeton said. “Daily administration of these peptide-secreting bacteria, called LrS235, significantly reduced clinical signs of the disease, including joint inflammation, cartilage destruction, and bone damage in an animal model of rheumatoid arthritis.”
The researchers tracked the LrS235 bacterium and the ShK-235 peptide it secretes inside the animal model. They found that after feeding rats live LrS235 which releases ShK-235, they could detect ShK-235 in the bloodstream.
“Another reason why we chose L. reuteri is that these bacteria do not remain permanently in the intestine. They are eliminated as the gut regularly renews its inner surface layer to which the bacteria attach themselves,” Beeton said. “This opens up the possibility of regulating the administration of treatment.”
LrS235 supernatants, but not LrGusA, blocked Kv1.3 currents and inhibited proliferation of human CCR7-TEM cells. (CREDIT: PNAS)
Further research is needed to bring this new drug delivery system into the clinic, but the researchers anticipate that it may make it easier to treat patients in the future. “These bacteria could be stored in capsules that can be kept on the kitchen counter,” Beeton said. “A patient could take the capsules on vacation without the need for refrigeration or carrying needles and continue treatment without the inconvenience of daily injections.”
The results provide an alternative delivery strategy for peptide-based drugs and suggest that these techniques and principles can be applied to a wider range of drugs and to the treatment of chronic inflammatory diseases.
LrS235 halts disease progression, reduces bone and joint damage and inflammation in rats with collagen-induced arthritis. (CREDIT: PNAS)
Other contributors to this work include Yuqing Wang, Duolong Zhu, Laura C. Ortiz-Velez, Jacob L. Perry, Michael W. Pennington, and Joseph M. Hyser. The authors are affiliated with Baylor College of Medicine, Pana Bio, Inc. or Ambiopharm Inc.
This project was funded in part by a pilot grant from the Alkek Center for Metagenomics and Microbiome Research at Baylor College of Medicine and Bridge Funding from Baylor College of Medicine. The work was also supported in part by the Cancer Prevention and Research Institute of Texas (RP180672, RP150578 and RP1806721 and RP170719), the National Institutes of Health (DK56338, CA125123, HG006348 and RR024574), the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.
For more science and technology articles, see our New Innovations section on The bright side of the news.
Note: The documents provided above by Baylor College of Medicine. Content may be edited for style and length.
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