Curing autoimmune diabetes  (TIDM) with HDAC (Histone deacetylase) inhibitors: Vorinostat-based therapy for autoimmune diabetes: Vorinostat (brand name: Zolinza and others), a histone deacetylase inhibitor used to treat cutaneous T-cell lymphoma (CTCL), increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and reverses TIDM, via up-regulation of its target gene, 27/June/2019, 11.54 pm

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Introduction: What they say

A study from the International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, “L. Sacco” Department of Biomedical and Clinical Sciences, University of Milan, Milan 20157, Italy; and Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA shows that “PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes.” This research paper was published, in the 15 November 2017 issue of the journal “Science Translational Medicine” [One of the best research journals in Science with an I.F of 15 plus], by Prof. Fiorina P and Nasr MB and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Curing autoimmune diabetes  (TIDM) with HDAC (Histone deacetylase) inhibitors:  Vorinostat -based therapy for autoimmune diabetes: Vorinostat (brand name: Zolinza and others),  a histone deacetylase inhibitor used to treat cutaneous T-cell lymphoma (CTCL), increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and reverses TIDM, via up-regulation of its target gene


From significance of the study to public health relevance:

Given that: (1) more than 422 million people worldwide are affected by Diabetes mellitus (DM); (2) Type 1 Diabetes (T1DM) constitutes about 5-10% (11 to 12 million) of all diabetic cases; (3) the incidence of T1DM is exponentially increasing year after year by 3%; (4) Diabetes is going to be one of the top 10 causes of death by 2030; (5) the life-long painful injection/drug treatment is required to treat DM; (6) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, while treatment for T1DM costs about $15 billion dollars per annum, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM;(ii) a side-effect-free natural product-based drug that does not harm or deplete adult stem cells; and (iii) a way to cure, not just treat, diabetes.


What is known?

Prof. Fiorina’s research team has recently shown that:(1) programmed death ligand 1 (PD-L1), the immune checkpoint regulator, is expressed poorly in hematopoietic stem and progenitor cells (HSPCs) of Type-1 diabetic (T1D) patients; (2) PD-L1 inhibits activated T-cells and thereby promotes immune tolerance; (3) the expression of PD-L1 is controlled by a network of miRNAs; (4) attenuating the expression of one of the miRNAs that target PD-L1 restores the expression of PD-L1 in HSPCs; (5) increasing the expression of PD-L1 in HSPCs, either genetically or pharmacologically, inhibits autoimmune response and reverses autoimmune diabetes; and (6) PD-L1 is expressed poorly in human HSPCs of T1D patients, suggesting that increasing the expression of PD-L1 in T1D patients may reverse and cure T1D.


From research findings to Therapeutic opportunity:

 Vorinostat/SAHA (Suberanilohydroxamic acid ) (brand name: Zolinza) is a histone deacetylase inhibitor. It is used to treat cutaneous T-cell lymphoma (CTCL) and others.  This study suggests that Vorinostat  may cure autoimmune diabetes (TIDM). Vorinostat, by increasing the expression of its target gene, it may increase the expression of PD-L1 and decrease the expression of TXNIP. Thereby, it may: (1) increase Regulatory T-cells(Tregs) function; and hematopoietic stem and progenitor cells (HSPCs); (2) decrease immune activation; (3) increase pancreatic-β-cell proliferation and regeneration; (4) increase the expression of genes that promote insulin sensitivity and insulin secretion;(4) decrease metabolic stress; and (5) promote glucose homeostasis (Fig.1).

Figure 1. Mechanistic insights into how Vorinostat inhibits the development of autoimmune diabetes (T1DM).  Vorinostat, by increasing the expression of its target genes, it may increase the expression of PD-L1 and other anti-diabetic genes. Thereby, it may prevent immune activation and attenuate the development of T1DM.

Figure 2. Vorinostat functions as an anti-hyperglycemic agent (in autoimmune diabetes) by up regulating the expression of PD-L1 and other anti-diabetic genes.

Figure 3. Histone deacetylase inhibitor Vorinostat promotes beta-cell regeneration and proliferation and prevents autoimmune diabetes.

Thus, pharmacological formulations encompassing “Vorinostat or its analogues, either alone or in combination with other drugs,” may be used to treat TIDM (Figs.2-3.).


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Undisclosed information: How does Vorinostat increase the expression of PD-L1?

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Amount: $750#

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References:

Web: http://genomediscovery.org or http://newbioideas.com

Citation: Boominathan, L.,  Curing autoimmune diabetes  (TIDM) with HDAC (Histone deacetylase) inhibitors: Vorinostat -based therapy for autoimmune diabetes: Vorinostat (brand name: Zolinza and others),  a histone deacetylase inhibitor used to treat cutaneous T-cell lymphoma (CTCL), increases PD-L1 expression, increases Tregs function, promotes immune tolerance, increases pancreatic β-cell proliferation and regeneration, increases insulin secretion, improves insulin sensitivity, increases energy utilization, and reverses TIDM, via up-regulation of its target gene, 27/June/2019, 11.54 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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