Patrick McCamphill

Patrick McCamphill, Ph.D.

Postdoctoral Associate

Research Interests

The main focus of my research is to study the neurobiology of Fragile X Syndrome (FXS) to find insights in the mouse model of the disease, which guide treatment in humans. A requirement for rapid mRNA translation at synapses for the stabilization of LTD, triggered by activation of metabotropic glutamate receptor 5 (mGluR5), has been well documented. Our lab has shown that LTD in a mouse model of fragile X led to the theory that excessive protein synthesis downstream of mGluR5 activation is pathogenic in FXS. This “mGluR theory of fragile X” has been validated in a variety of animal models and therapies based on this work have been through large-scale clinical trials from Novartis, Roche, and Seaside Therapeutics. While these trials ultimately failed to demonstrate that the treatments worked, many of these families reported exciting improvements.

Why did these trials fail? One potential explanation is that tolerance rapidly develops to the drugs, so they lose their effectiveness. Indeed, some caregiver reports have suggested some early improvement that did not continue for the length of treatment. In 2005, Robert Bauchwitz and colleagues showed that an experimental compound that blocks mGluR5 protected Fragile X mice from seizures. But this effect faded quickly with chronic treatment, suggesting that the mice developed tolerance to the drug. The first goal of my research study is to understand this drug tolerance to mGluR5 antagonists in Fragile X mice and to explore approaches to avoid or reduce it.

I am investigating if tolerance develops to a range of other drugs that show promise for Fragile X, including arbaclofen (a GABA-B receptor agonist) and GSK3 inhibitors. Development of tolerance may explain the disappointing clinical results obtained to date with a range of drugs. The possibility of tolerance has been relatively neglected in preclinical studies to date, so I am comparing durable efficacy of three different pharmacological treatments that target different stages of the aberrant signaling pathways in Fragile X mice.

Education

Ph.D. in Neuroscience –McGill University – 2015

B.Sc. in Molecular Evolution– Acadia University  – 2003