Trending: RAGE and Type 1 Diabetes
Dr. Josephine Forbes is a distinguished researcher and an Honorary Professor for the Mater Research Institute in South Brisbane, Australia and Program Leader for the Chronic Disease Biology and Care Research Team. A National Health and Medical Research Council (NHMRC) Senior Research Fellow, Dr. Forbes began her medical career in pediatric nephrology before partnering with JDRF among others, to work on diabetic complications and later transitioning to focus on the intersection between advanced glycation, mitochondria[JF1] and diabetes. We spoke with her from her home in Brisbane, and found her enthusiasm for her work to be inspirational.
Some background: RAGE is a 35kD transmembrane pattern recognition receptor of the immunoglobulin superfamily, implicated in inflammatory disease, and is expressed on multiple cell types including T cells. Glycation end products (AGEs) are bound by RAGE. Also known as glycotoxins, AGEs are a varied group of highly oxidative compounds that are pathologic in diabetes. Foods that have been exposed to high temperature are very high in these compounds. AGEs give processed foods brown/yellow color, aroma, taste and long shelf life, and there has been an escalation in AGE in food since the 1970s.
sRAGE is soluble RAGE and it is an antagonist that competes for RAGE ligands, or AGEs.
When bound to their receptors, AGEs cause inflammation and oxidative damage.
to RAGE and sRAGE
We began our interview with a shout out to the new paper published in bioRxiv by Dr Forbes and her team, “Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes”. https://doi.org/10.1101/2020.01.10.902627
The interview unfolded as follows with some editing for brevity.
JF: We first saw a change in islet function and increase in immune cells around islets in mice after increasing AGEs in their diet. This was unexpected. We wondered, “What if we inhibit AGEs in mice?” This experiment showed a slowed progression to Type 1 diabetes (T1D) in mice and we decided to pursue humans.
Our group and one in the UK showed elevated AGEs in those at risk (1+ biomarkers) that progress to T1D. This was a good risk prediction model, and we turned our investigation to RAGE. Most of this work was done in Finland. The RAGE gene (chromosome 6) lives in the HLA region. To control for that, we matched patients for HLA risk and STILL saw a RAGE effect. It wasn’t proof, but it gave us confidence to continue.
The gene for RAGE is associated with certain polymorphisms; two characterize increased risk for T1D, while one is highly protective against T1D. We noted that one of the polymorphisms that imparted risk was associated with a certain profile of a T1D patient just prior to diagnosis. We also noted in this same cohort, patients had high levels of AGE and lower than normal sRAGE[JF2] when they develop an immune response against themselves, termed “autoimmunity”. We wondered, could we just stabilize autoimmunity by giving sRAGE in this window? For 2 weeks we gave sRAGE then stopped. Results in the preprint showed that the sRAGE went back to normal ranges and the progression to T1D was also prevented. The surprise finding was that Tregs were expanded and this opened the door to a partnership with Kevan Herold (Yale) which is backed by JDRF.
In this collaboration we are testing a RAGE antagonist. There is a known compound but that was tested by Pfizer and vTv Therapeutics for Alzheimers. JDRF helped connect us to the companies and solidify the collaboration, so they were fantastic with that. This first trial will finish in Sept 2020 and will identify whether this compound works like sRAGE did in humans.
TSS: Hypothetically, if you gave the new compound to a T1D patient who is 5 years post diagnosis, what might happen?
JF: A lot of devastation comes after T1D diagnosis and the idea that anything that can prolong the life of beta cells, change immune function and reduce their risk for complications would be beneficial. It’s possible that this compound can do this.
TSS: Can you comment on the potential role of sRAGE in decreasing fibrosis/increasing the length of time in body for a beta implant like those in production by Semma, Sigilon and Viactye ?
JF: There is a lot of work going on in the kidney space that is potentially translatable. In Australia, Prof Toby Coates was involved in creating “skinsulin”. This was a result of the serious burn cases in the Bali bombing. They built a matrix for growing a person’s skin cells and have adapted it to islets. It’s in clinical testing at the moment, but the benefit is you could give topical immunosuppression on the spot”. Of course, opportunities for collaborations must be funded. The Australian government (and JDRF I believe?)[JF3] has been great about funding these types of out of the box collaborations.
TSS: Can you comment about the dietary increases in AGE since the 1970s and the clinical presentation you are observing?
JF: That’s an important correlation. Right now, Australia is conducting the Environmental Determinants of Islet Autoimmunity (ENDIA) Study. It’s an observational study, powered to look at environmental factors, following 1500 triplets from birth to 3 years of age. These babies have family with T1D but don’t necessarily carry HLA risk. Factors like viruses, microbiota and AGE and RAGE are part of it, with high risk for T1D (> 2 autoantibodies) and T1D as the primary endpoint[JF4] . It will finish in ~2022.[JF5]
TSS: Can you name some other scientists in Australia that are making an impact in T1D research?
JF: There are many fantastic Australian Scientists including Toby above, but two come to mind in the viral space. Maria Craig in Sydney is looking at viral interface with gut, skin, respiratory system. RAGE is expressed highly in these areas. Len Harrison has shown stabilization of T1D with rotavirus vaccine. That’s not anecdotal, but certainly significant.
TSS: Can you comment about the decrease in gut microbial diversity in patients at the time of T1D diagnosis and RAGE?
JF: Its speculative, but the gut has a high number of RAGE receptors. Another distinguished up and coming Australian scientist (my old post doc), Melinda Coughlan is looking at this. Some AGE are absorbed into the circulation but many are not and interact with bacterium in the gut. She has seen a change in microbiota associated with high/low AGE diets.
TSS: What’s next for you and your lab?
JF: We are looking at complications that arise in young people 15-25 years old, and asking whether the risk for their particular complication was there at diagnosis. This age group historically has poor blood sugar control due to growth needs during this time, but we are asking whether certain individual pathways are differently activated from the start. We’re thinking about how early can we say they “have” kidney disease and can we intervene.
Also, we are looking at therapies which target mitochondria. My hunch is that one of the underlying risks for complications could be mitochondrial dysfunction.
TSS: Thinking about the multifactorial nature of T1D, and the fact that we’ve been trying to solve it for about 100 years, what do you think of a retrospective historical analysis of all the papers on T1D by AI? There would have to be a consortium of researchers to design the algorithms, and big companies like Verily and Deep Mind could potentially run them.
JF: Completely agree with that. That’s why the publication of negative data is so important, that’s where the algorithm can pull something from it. We can’t possibly know all the literature. I read very widely but I come across papers that still surprise me and think “How did I miss that”?
TSS: Thank you so very much. We are planning on offering a space for scientists to share negative data on our new platform, thesugarscience.com. It was a pleasure speaking with you and thank you for all you are doing to cure Type 1 diabetes.
To learn more: Josephine Forbes Lab
[JF1]I added this in here because JDRF also support this work and we are planning a Phase 1b on this mitochondrial space with JDRF support hopefully beginning next year J
[JF2]when they develop antibodies against themselves called autoimmunity?
[JF3]I think this group have support that was won from the Australian Govt and given to the JDRF Australian Type 1 Diabetes Clinical Research Network? JDRF Australian have lobbied our govt hard for this money and it has been used for many great things. It helped build my diabetes and kidney/cardiovascular compounds into a Phase 1b trial.
[JF4]The endpoint is persistence of two or more known T1D autoantibodies or diagnosis of type 1 diabetes. This is only because ethically ENDIA were not allowed to only have T1D as the endpoint.
[JF5]Actually I was talking here about ENDIA (environmental determinants of islet autoimmunity) which is an Australian study looking at similar things 1500 triplets.