UHealth - University of Miami Health System

Peter Buchwald

General Information

Peter  Buchwald

Contact

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Languages

  • English

Roles

  • Associate Professor
  • Director, Drug Discovery

Research Interests

Current research within our drug discovery program at the Diabetes Research Institute (DRI) is mainly focused on immune-modulatory therapies intended to prevent or reverse type 1 (insulin-dependent or juvenile-onset) diabetes (T1D) or to benefit islet cell transplant recipients. Even with well-managed insulin therapy, chronic and degenerative complications still occur in a considerable fraction of T1D patients. In the meantime, all existing therapeutic agents tested in large-scale human clinical trials have failed to stop the progressive decline of the function of the insulin-producing pancreatic β-cells in T1D patients. Hence, there is a considerable therapeutic need for safe and effective immune interventions that could prevent or reverse T1D without causing unacceptable side effects. Research in our group is focused on several different strategies, including (i) identification of small-molecule modulators for costimulatory protein-protein interactions within the TNF superfamily (such as CD40-CD154), (ii) targeting of Smad7 on the TGF-β pathway using an antisense oligonucleotide approach, and (iii) quantification and modeling of glucose-stimulated insulin secretion and islet function in general.

 
(i) TNF superfamily receptor-ligand interactions such as CD40-CD40L or OX40-OX40L are promising therapeutic targets for immune modulation. However, while the blocking of such protein–protein interactions (PPIs) is relatively easy with antibodies, it is particularly challenging with traditional drug-like small molecules. We have identified the first published small-molecules that inhibit the CD40-CD40L PPI, and, more recently, also the first small-molecule modulators of the OX40-OX40L interaction. Ongoing work is focused on developing novel, more specific, and more drug-like compounds that can serve as lead candidates to develop clinically useful therapeutics.
 
(ii) Smad7 is a negative feedback regulator of the TGF-β pathway and a novel therapeutic target in autoimmune diseases. We have obtained very promising results targeting this pathway using an antisense approach. In the stringent model of reversal of hyperglycemia in NOD mice, where treatment is started only following onset of hyperglycemia (when 80-90% of the β cell mass is already lost), Smad7 AS treatment reversed hyperglycemia in more than half of treated animals, and this reversal persisted long-term even after treatment was stopped.
 
(iii) A major obstacle of current islet transplant-related clinical and research projects is the lack of reliable, reproducible, and cross-platform standardizable methods to assess islet mass and islet function. To improve this situation, we are working on the implementation of a fully automated digital image analysis (DIA) islet mass (IEQ) counting method that can met cGMP requirements as well as on the extension of our computational insulin secretion model calibrated via dynamic glucose-stimulated insulin release (GSIR) perifusion assays of free and encapsulated islets.

Awards

AAAS Fellow

Education

1997 Ph.D.
University of Florida
1986 B.S.
"Babes-Bolyai" University

Publications