Activating islet NAMPT to improve islet transplant outcomes

Daniel Egbase, King's College London

 

Aims

Islet transplantation is promising treatment strategy for type 1 diabetes (T1D), which has the potential to reduce or eliminate requirement for endogenous insulin therapy. Consequently, islet transplantation can reduce risk of acute-complications of insulin therapy, (e.g. hypoglycaemia), and improve long-term glycaemic control, reducing onset of diabetic complications¹. However, graft failure, particularly immediately after transplantation, limits long-term success of this treatment, and identifying novel strategies to improve graft survival is essential¹.

Our preliminary studies show that activation of NAMPT, a key enzyme for NAD biosynthesis², with SBI-797812³, protects against inflammation-mediated death and dysfunction in isolated mouse and human pancreatic islets. Moreover, NAMPT activation can reverse inflammation-mediated increases in expression of genes associated with islet allograft rejection, and islet apoptosis and inflammation. We hypothesise that NAMPT activation can improve transplanted graft survival.

Aims:
To examine whether NAMPT activation can improve:

(a) function,

(b) survival

of mouse islets transplanted into diabetic mice.

This project will determine whether NAMPT activation can improve islet graft survival and function in pre-clinical T1D models, generating proof-of-concept data to support development of NAMPT activators for improvement of islet transplantation in T1D.

1)Shapiro et al, Nature reviews Endocrinology,13:268-277(2017)

2)Imai S. Current pharmaceutical design 15:20-28(2009)

3)Gardell et al, Nature Communications,10,3241(2019)

 

Grant awarded: £4,800.00