A Molecular Approach to Clinical Trials

Palo Alto, CA — How can physicians and scientists make clinical trials faster, cheaper, and more likely to succeed? The answer may be proteomic analysis. This largescale study of proteins is showing the real time molecular makeup of blinding eye diseases and revealing specific diagnoses that can determine an ideal therapeutic regimen. 

Dr. Mahajan, Associate Professor of Ophthalmology at Stanford University, believes that proteomics can transform clinical trials by identifying only those patients most likely to benefit. 

Standard clinical trials enroll hundreds of patients to test new drugs. This is because clinical diagnoses are imprecise, and the enrolled patients are typically a mixed population with variable disease origins, disease stages, and disease severity. Some may even be misdiagnosed. In contrast, highly focused trials with just a few patients are possible in the case of genetic diseases, since there is a precise molecular marker available to select the few patients likely to respond to therapy. 

The Mahajan lab reasoned that highly focused clinical trials for common, non-genetic eye diseases can now be designed around protein biomarkers found in eye fluids.

In the article, “Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease,” lead author Gabriel Velez, a graduate student in the Mahajan lab, details how surgical sampling of eye fluids for protein analysis is transforming eye research and patient care. 

“With our new technological advances in protein analysis”, Velez noted, “key ophthalmic protein biomarkers can be used to precisely diagnose eye diseases such as uveitis, macular degeneration, cancer, retinitis pigmentosa, proliferative vitreoretinopathy, diabetic retinopathy.” 

“A molecular diagnosis by proteomic analysis should be a prerequisite for enrollment in clinical trials,” Mahajan emphasized. “We should now include only patients that have the molecular target of the experimental drug being tested and exclude patients without the drug target. This would dramatically shrink the pool of necessary volunteers.” 

The use of molecular diagnosis tied to the drug being tested would also lower the cost of clinical trials making them more attractive and easier to fund.

Mahajan emphasized, “Proteomic analysis can streamline all clinical trials, take the guess work out of prescribing medications, make treatment more effective, and lower costs.”

Analyzing the proteins in only a few drops of eye fluid has helped to diagnose patients and select the right drugs at the right time, and it has revealed the new molecules researchers should be targeting. 

Velez said, “Once we have a molecular target in our sights, numerous molecular drugs may already be available to us. We showed this in a recent study on Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV), an inherited, progressive inflammatory eye disease with few therapeutic options.”

Before the Mahajan lab  study, ADNIV patients were treated with non-specific immunosuppressive medications that had undesirable side effects. Proteomic analysis of ADNIV vitreous by Mahajan’s team revealed that TNF-α levels were normal, explaining why infliximab therapy had previously failed in these patients. Instead, they found that ADNIV vitreous contained abundant levels of other known drug targets: VEGF, T-cell proliferative markers, and IL-6. Based on these proteomic data Mahajan’s team repositioned bevacizumab (anti-VEGF monoclonal antibody), intravitreal methotrexate (T-cell inhibitor), and tocilizumab (anti-IL-6 monoclonal antibody) and successfully mitigated the bleeding, inflammation, and scar tissue formation in these patients.

Proteomics can explain why some clinical trials have failed, as seen in the ADNIV study. It can also be seen in the initial treatments for intraocular scar tissue formation (Proliferative Vitreoretinopathy). A trial of steroid injections failed to stop intraocular scar formation. A second trial using an antibody against the VEGF protein also failed.  When the Mahajan lab analyzed eye fluid samples from patients with intraocular scar tissue, they noted there were no steroid sensitive proteins. They also found that VEGF was only present very early, but patients in the trail had been treated late. Since doctors did not know this, they selected the wrong drug and used a drug at the wrong time.

Mahajan concluded “Proteomic profiles might represent the ultimate biomarkers of cellular status in health and disease. Recasting eye disease in molecular terms will allow us to take innovative approaches to curing blindness. Eye surgeons can now think like molecular biologists.”