Clinical Trials, CRISPR, and Big Data

By Michael Tranfaglia, 11/1/2016

FRAXA’s mission is to find effective treatments and ultimately a cure for fragile X by accelerating the pace of research. We can think of this like a major highway construction project: we aim to speed the flow of traffic (research) by eliminating bottlenecks along the route. Even the most complex processes have obvious choke-points that limit flow through the system. If these bottlenecks can be relieved, everything moves a lot faster.

This has been FRAXA’s approach to fragile X research for quite some time, and we have been successful at speeding things up in this way.

Early Bottlenecks

In our early years, little was known about the causes and effects of fragile X. So we funded basic research. The field was the province of molecular biologists and geneticists. So we recruited neuroscientists. FRAXA's booth each year at the enormous (30,000 scientists!) Society for Neuroscience conference, combined with FRAXA Investigators Meetings and Gordon Research Conferences, attracted much new talent to the field. Fragile X is a hot topic in neuroscience today, and thousands of scientists around the world are studying topics related to fragile X. Basic fragile X research is no longer a bottleneck, and so it is now a lower funding priority.

Other past bottlenecks, such as difficulties obtaining animal models and antibodies, have been resolved by targeted resource grants like the FRAXA Mutant Mouse Resource at Baylor College of Medicine, which distributes mice to scientists worldwide. These grants have ignited an explosion in translational research in fragile X, leading to many promising therapeutic strategies now being investigated.

The main log jam then moved further down the road to the preclinical stage of the development process. So FRAXA developed standardized methods to validate promising new drugs, with much higher throughput and vastly greater efficiency, like the fragile X drug validation initiative (FRAX-DVI) in Chile and Argentina.

On to Clinical Trials

With the preclinical bottleneck essentially resolved now, the current bottleneck is clinical trials.

In recent years, we’ve recruited and advised pharma industry partners who have invested tens of millions of dollars in fragile X clinical trials of investigational drugs (companies like Neuropharm, Novartis, Roche, Seaside, Alcobra, and Neuren.) This is one way to bring new fragile X treatments to market. But we also have a growing list of available drugs that have shown promise in preclinical testing, but are still waiting for clinical trials. Because these drugs are already on the market, few companies have any motivation to fund trials. While trials designed to obtain FDA approval for new drugs or new indications are very expensive, trials of available drugs in fragile X can be done on a smaller scale by clinical researchers for far less money. This is a great value, but the costs must be borne primarily by the fragile X community.

In 2016, FRAXA funded three clinical trials, in Quebec, Barcelona, and Antwerp. The newest of these, in Quebec, is the first trial of a combination of disease-modifying agents (lovastatin and minocycline), in Fragile X. We’ve also funded two studies of biomarkers in people with Fragile X (in addition to several projects looking to identify biomarkers in animal models.)

In 2017 we are launching FRAXA Clinical Trial Grants. From now on, all of our larger grants will be reserved exclusively for clinical research with fragile X subjects!

Available Drugs and Other Opportunities

At the same time, advances in technology have opened up new strategies. Drug repurposing is the application of approved drugs to treat new diseases. We have contracted with a leading company in this field, Healx, to conduct an in-depth study of biological changes caused by the fragile X mutation and match those changes to the known effects of all available drugs, via sophisticated computer algorithms. This big data match-making approach to drug repurposing has the potential to reveal treatments for fragile X that can be clinically useful right from the start.

We’re also funding efforts to fix fragile X at the most basic level, by reactivating the silenced FMR1 gene. FRAXA is funding groundbreaking studies using the latest technologies like CRISPR, Xi, and iDRiP to restore the function of the fragile X gene in boys and girls with the full mutation.

We’ve paved a lot of road, and sometimes it seems like our version of the Big Dig will never be done. But this is the last bottleneck. Successful clinical research gives us actual treatments for our kids, so we think it’s time to make this our top priority!

DNA-secret of Life, by James Watson - toward a cure for fragile X

Dr. James Watson, winner of the Nobel Prize in Medicine and member of FRAXA's scientific advisory board, wrote:

“Studies of fragile X have been galvanized by those most directly affected … experience shows that dedicated, resourceful, and, above all, motivated organizations like FRAXA sometimes do hold the key to cracking these diseases.” (DNA – The Secret of Life, by James Watson)