The abstract for the paper that Fairbanks CEO Dr. Alan Schneyer would have been discussing at the canceled ENDO 2020 meeting in March has now been published in Journal of the Endocrine Society. The abstract is titled “FSTL3 Neutralizing Antibodies Restore Function to Diabetic Mouse and Human Islets: A New Approach for Treating Diabetes”.
The studies that would have been presented include a determination of how the therapy works on its target FSTL3 as well as a demonstration that the therapy can restore insulin secretion to diabetic beta cells. Animal studies are underway that hopefully will lead to human trials in the not too distant future.
On Sunday, June 24th, Fairbanks Pharmaceuticals CEO Dr. Alan Schneyer presented a poster at the American Diabetes Association meeting in Orlando entitled “FSTL3 Inhibition Restores Glucose Responsive Insulin Secretion In Non-Functional Human Islets”.
The poster describes identification of FSTL3 neutralizing monoclonal antibodies, verification of their specificity and ability to inhibit FSTL3 binding to activin A and B as well as GDF11, and the ability of these antibodies to disrupt pre-formed FSTL3-activin complexes that otherwise are stable.
Also shown was experiments in which human islets that lost their ability to secrete insulin in response to glucose (the most critical contribution of the beta cells) were restored to glucose responsiveness after exposure to Fairbanks’ antibodies. These results support further development of this FSTL3 neutralizing approach as a novel therapy for diabetes.
Fairbanks Pharmaceuticals was selected as a semi-finalist for this year’s Diabetes Challenge competition. The poster pictured above was submitted for display at the May 21st event that will include a pitch competition among the finalists.
The poster first emphasizes that diabetes is caused by inadequate production of the hormone insulin and, critically, that insulin comes only from cells called beta cells. In type 1 diabetes, beta cells are destroyed by a patient’s immune system leaving them without insulin for the rest of their lives. In type 2 diabetes, which affects 95% of diabetic patients, beta cells gradually lose insulin production for a variety of reasons and eventually fail to secrete enough insulin to control blood glucose, leading to a host of associated maladies. Fairbanks Pharmaceuticals is developing a new type of therapy that will restore function to these beta cells and over time, induce regeneration of new beta cells in order to restore natural insulin production.
The next panel shows the scientific evidence that led to this therapeutic strategy. A protein called FSTL3 regulates growth factors in the TGF-beta family known as activin, GDF11, and myostatin. By eliminating FSTL3 in mice we found that their islets were doubled in size and they contained many more beta cells. This allowed them to more easily control blood glucose and were more sensitive to insulin that was produced by these beta cells (red lines on graphs on right side). This suggested that a therapy which could completely block FSTL3 might induce more beta cells and better insulin production, the basis for Fairbanks’ therapy.
On the right side of the poster is our research and development team as well as our scientific advisory board that includes basic scientists who are experts in FSTL3 and the TGF-beta family, diabetes clinicians who are also researchers, and diabetes clinicians who have successfully developed drugs for diabetes.
Below that is a panel showing that Fairbanks has produced at least 1 antibody that can neutralize FSTL3 (FP-101). In one test of its activity, this antibody was used to treat human islets (containing beta cells) that behaved like defective diabetic islets. After 24 hours of treatment, the defective islets regained their ability to secrete insulin in response to elevated glucose, suggesting that the antibody could restore diabetic islet function as proposed. This also indicates that the FSTL3-activin system is functional in human islets.
Finally, the last panel indicates that Fairbanks has applied for a patent and funded its work so far with personal funds, a Phase 1 SBIR grant (completed April 2017) and is awaiting the imminent start of our Phase II grant.
Fairbanks scientists collaborated with UMass-Amherst faculty to determine whether the increase in insulin-producing beta cells observed numerous times in FSTL3 knockout mice results, at least in part, from enhancing alpha to beta cell transdifferentiation. A process called “lineage tracing” in which alpha cells are permanently marked with a yellow tag was used to monitor their fate over time. Alpha cells typically produce glucagon, a hormone that counteracts insulin and helps prevent glucose from falling too much. Yellow cells that now produce insulin (a hallmark of beta cells) were identified in wild type mice and the number of these cells was increased significantly in mice in which the FSTL3 gene was inactivated (FSTL3 Knockout mice) that have elevated activin signaling.
These results support our hypothesis that activin and related growth factors enhance alpha to beta cell transdifferentiation resulting in increased numbers of functional beta cells.
These results were published in the journal Endocrinology in March 2016 (Endocrinology 157: 1043–1054, 2016). View in Pubmed
The transcription factor Arx is required to form pancreatic islet alpha cells while the factor Pax4 is required to specify beta cells. Reducing Arx expression in alpha cells is sufficient to turn them into beta cells.Fairbanks scientists have collaborated on new research published in Endocrinology showing that activin directly suppressed Arx and increased Pax4 expression, consistent with our hypothesis that increased activin signaling promotes alpha to beta cell transdifferentiation.
Since FSTL3 knockout mice have increased activin signaling, these new results suggest that the enhanced beta cell formation in FSTL3 knockout mice could be due to activin-assisted transdifferentiation from alpha cells. More research is needed to determine if this process occurs naturally and amenable to intervention as a basis for developing novel diabetes treatments.
Fairbanks Pharmaceuticals scientists collaborated on a recently published study in which the hormone activin was applied to human islets from donors who had type 2 diabetes. In untreated islets, glucose failed to stimulate insulin secretion as one would expect in diabetes. But in the activin treated islets, elevated glucose stimulated insulin release to levels seen in normal islets in the absence of activin.
This is important because of another part of this study in which gene expression was compared between normal and diabetic islets. Activin production is very high in normal islets but reduced by 50% in diabetic islets. Critically, the activin inhibitor, FSTL3, is expressed at 8-fold greater levels in diabetic islets compared to normal. This means that functional activin (activin not inhibited by FSTL3) is much lower in diabetic islets. This suggests that one defect in diabetic islets is loss of activin signaling and when that activin is restored, insulin release returns to normal.
Fairbanks Pharmaceuticals is developing technology that will inhibit the action of FSTL3. Therefore, the newly published research suggests that this technology could have important therapeutic effects in patients with diabetes to enhance insulin release and restore more normal glucose control.
In order to determine the function of Follistatin Like-3 we created knockout mice in which the gene that codes for this protein was disabled. Mice without FSTL3 had larger pancreatic islets and improved glucose control suggesting that loss of FSTL3 might be beneficial for patients with diabetes. We continued our analysis of these mice and found that the increased number of insulin producing beta cells was not due to increased proliferation of the existing beta cell population.
Our current research is focused on whether loss of FSTL3 stimulates a process where other cell types in the pancreas, such as alpha cells, change their fate and become beta cells, a process known as transdifferentiation or reprogramming. Regardless of the actual mechanism, however, Fairbanks Pharmaceuticals is focused on development of new diabetes therapies based on altering FSTL3 function.