How Do Research Discoveries Translate into Clinical Cures?

Scientific research drives discovery into novel biological pathways that regulate normal bodily functions and can indicate alterations that may play a role in autoimmunity, cancer and other diseases. Understanding of the cells, molecules and genes involved in these pathways can lead to the development of drugs, cell therapies, devices and other technologies that might enable prevention, modification, or reversal of disease. But how do scientists take laboratory findings and translate them into people?

Central to the DRI is having the infrastructure and scientists to take research from the test tube to animal models to clinical trials. Over the years, many discoveries have been made that have advanced the field of biological replacement therapies. When I undertook my second post-doctoral fellowship at the DRI, islet cell transplantation led to 10% insulin independence at one-year post-transplant. Today, under the direction of Dr. Camillo Ricordi and collaborators around the world, one year insulin independence is greater than 90% and long-term transplant survival of many years has been achieved. Two areas remain pivotal to finding a biological cure: a widely available source of insulin producing cells and safer, more effective immune intervention agents that prevent rejection of transplanted cells.

One way that research findings are translated is through early-stage clinical trials, which are often undertaken at universities. The DRI is very active in clinical trials focused on a biological cure, intervention at the onset or in the prevention of type 1 diabetes (T1D). The Diabetes Prevention Trial (DPT), led by Dr. Jay Skyler, was groundbreaking in determining methods for predicting those at risk for T1D and in the launch of clinical trials to intervene at onset of T1D. DPT was followed by Type 1 Diabetes TrialNet, initially led by Dr. Skyler, and trials continue at the DRI today. DRI’s Carlos Blaschke kindly spent time with me detailing the ongoing studies in this area, many of which are supported by the NIH funded TrialNet consortium. In one study, patients with recent onset T1D were treated with an antibody that targets the T cells that attack and destroy beta cells. This resulted in the first demonstration that T1D progression can be delayed for a median of two years and follow up of those patients continues. In a separate trial, aimed at prevention of T1D, an agent that blocks a key signaling pathway in T cell activation was targeted; enrollment for this study is complete and patients continue to be observed to determine if T1D will be delayed.

In the area of a biological cure for T1D, the DRI has led the way in clinical trials, and the  NIH funded Clinical Islet Transplant Consortium, led by Dr. Ricordi, demonstrated that islet cell transplantation can lead to long-term insulin independence, improvement of the complications of diabetes and a reduction in severe hypoglycemia requiring assistance. Broad based application of a biological cure remains dependent on 1) identification of alternative insulin producing cell sources (as are only 2-3 thousand pancreas donors in the US – not enough insulin producing cells to treat all T1D patients) and 2) safer, more effective immune intervention agents. The DRI has been actively engaged in a clinical study involving transplantation of stem cell derived insulin producing cells, utilizing currently accepted immune intervention for islet transplantation. Dr. Ricordi recently presented the findings at the EASD meeting in Europe, including data on a DRI patient transplanted in a phase 1 (safety) / 2 (efficacy) trial with Vertex’s VX-880 (stem cell derived insulin producing cells), and the results are compelling. Utilizing the current standard immune intervention for islet transplantation it was reported that the patient who received the Vertex cells was off insulin at 270 days, with an A1c of 5.2, no hypoglycemia and 99.9% time in range for glucose levels. This data establishes proof-of-concept and supports further development of VX-880.

Many collaborations with industry also occur in preclinical models, including in the labs of Drs. Kenyon and Berman. The team has demonstrated that a new antibody aimed at blocking a key immune pathway (anti-CD40L, Eledon Pharmaceuticals) is safe and effective; the antibody is now beings tested in clinical studies. The team is also testing genetically modified pig islets as an alternative source of insulin producing cells (eGenesis). The conformal coating technology of Dr. Alice Tomei was licensed to Sernova, which is supporting collaborative work with Dr. Tomei to further develop the approach for clinical application. Several other collaborations between the DRI and industry are ongoing to test novel technologies in preclinical models.

Our relationship with companies that support the large-scale production of cells and immune intervention agents that can lead to a safe and effective biological cure is critically important. Whether we engage with startups pursuing novel agents for immune intervention or companies focused on devices that can deliver local immune intervention and protect islets, our engagement with companies is essential for taking ground-breaking research from the test tube to those patients who need it.

We are at a transformational crossroads in this regard, with many companies engaging in the development of stem cell derived insulin producing cells and novel immune intervention agents that have shown significant promise. It will still take time, but advancements that we only dreamed of 10 years ago are turning into reality. As a parent and a scientist, I am energized by the current studies and the future potential.

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