Developing a Pill That Mimics Effects of Gastric Bypass Surgery Interview with:

Jeff Karp B.Eng. PhD. Professor of Medicine Center for Nanomedicine and Division of Engineering in Medicine Brigham and Women’s Hospital, Harvard Medical School Boston MA

Prof. Karp

Jeff Karp B.Eng. PhD.
Professor of Medicine
Center for Nanomedicine and Division of Engineering in Medicine
Brigham and Women’s Hospital
Harvard Medical School
Boston MA How would you briefly explain the most important findings and conclusions of this study to a non-expert?

  • The type-2 diabetes (T2D) epidemic will affect over 642 million people worldwide by 2040. As a result, diabetes costs the US healthcare over $174 billion dollars annually and is the leading cause of blindness, amputations, renal failure, and poor cardiovascular outcomes. Recently, bariatric surgery, bypassing stomach and intestine from the food stream, has shown promising results and shown to be superior to pharmaceuticals in managing T2D. However, the risks of surgery along with permanent changes to gastrointestinal anatomy deters many suitable patients from surgery, with less than 1-2% of Americans who qualify for weight loss surgery actually undergoing the procedure. Therefore, there is an urgent need for a safe, non-invasive and effective treatment for wider diabetic patient population.
  • We envisioned a pill that a patient can take before a meal that transiently coats the gut to replicate the effects of surgery. During the past 8 years, we’ve been working on this idea and have developed a safe gut-coating material that can potentially mimic the beneficial effects of gastric bypass procedures in the form a pill.
  • LuCI can be activated in any part of gastrointestinal tract (e.g. stomach, duodenum, intestine, colon) to form a temporary physical barrier that isolates that part of gastrointestinal tract. In our pre-clinical models, LuCI coated the duodenum to modulate glucose responses in oral glucose tolerance tests.
  • These beneficial effect are observed without any evidence of systemic absorption of the drug.
  • We believe that LuCI could be a new therapeutic approach for T2D that is based on Roux-en-Y gastric bypass surgery, but is safer, associated with significantly less complications, and thus can potentially help a wide T2D patient population.
  • In a separate set of studies, we also showed that luCi allows delivery of certain proteins and drugs, which would normally be degraded by the gastric acid, to the GI tract, protecting it from gastric acid digestion and prolonging their luminal exposure. Why is it challenging to deliver drugs to the mucosa of the small intestine?

  • There are series of biological barriers present from mouth to the target site in small intestine. First, the harsh environment in the stomach including its highly acidic environment and the presence several enzymes denatures protein based drugs, and proteolytic enzymes present in the duodenum and intestine further degrade proteins – – thus the proteins lose their structure and function. Given the lack of effective delivery systems for such drugs, they are currently administered parenterally (e.g., intravenous injection).
  • The gut-targeting platform that we have developed can be loaded with protein therapeutics and taken orally.  The system protects  the drugs from denaturation. Are there any drawbacks of the material or how do you think LuCl could be improved even more (e.g. in terms of drug delivery; combination with other materials or particles)?

 Response:  The material we have developed is a derivative of a very safe FDA approved drug used in millions of patients. To date we have demonstrated a robust response in modulating glucose absorption in rats.   We need to demonstrate next that this in diabetic models and in humans. Apart from type II diabetes, are you envisioning any other possible applications? 

Response: Several diseases such as inflammatory bowel disease (IBD) affect the mucosal surface of the bowel, yet direct localized drug delivery to the affected mucosa is challenging. Drug delivery systems that can directly deliver drugs to the targeted regions of the gut with minimal systemic exposure would provide significant advantages including prolonged drug efficacy, lowered dosing frequency, and decreased side effects. We showed that LUCI can protect biological agents from the harsh conditions in the stomach and extend the duration of exposure to gut tissue.  Are there already plans to take the material and method to the next step (preclinical and clinical trials)?

Response:  LuCI is based on a safe FDA-approved compound with minimal modifications, and exhibits an excellent safety profile with no systemic absorption. Our next goal is to test LuCI in a diabetic model and demonstrate long-term impact on the remission of type-2 diabetes.

Citation: Yuhan Lee, Tara E. Deelman, Keyue Chen, Dawn S. Y. Lin, Ali Tavakkoli, Jeffrey M. Karp. Therapeutic luminal coating of the intestine. Nature Materials, 2018; DOI: 10.1038/s41563-018-0106-5 

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