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5 Challenges and Opportunities Despite the fact that glutamate is a key excitatory neurotransmitter which plays an important role in many central nervous system (CNS) dis- orders, few biomarkers have been developed to provide objective measures of diagnosis, treatment, and/or prognosis for glutamatergic diseases. The few biomarkers tied to glutamate function have not advanced far enough to allow for simple “go/no go” measures of drug effect on glutamate in the brain. Workshop participants highlighted four key features of the glutama- tergic system that are hurdles for biomarker research: • T he diversity of glutamate’s functions and the ubiquity of its ex- pression in CNS pathways can lead to widespread pathology and greater likelihood for adverse effects with non-specific treatment; • T he plasticity of the glutamate synapse is an important feature of glutamate transmissions, but can be highly damaging and difficult to control in disease states; • G lutamate physiology versus pathology depends on relatively mi- nor differences in glutamate concentrations; and • T ight control over normal glutamate neurotransmission is exerted by at least 30 proteins found at the synapse. Targeting one or more of these proteins can trigger feedback mechanisms that might ne- gate the intended effect. The complexity of this system presents a formidable barrier to devel- oping glutamate biomarkers, making glutamate-related diseases difficult to treat or prevent. However, embedded within the complexity is tremendous 33

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34 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT opportunity, as shown by identification of countless targets and emerging new scientific techniques. CHALLENGES Over the course of the workshop, participants noted several challenges to the development of glutamate-related biomarkers. They include • F ew pharmacological ligands in animals or humans are available to probe the glutamate synapse. Few radiotracers exist for imaging glutamate function, especially through positron emission tomogra- phy (PET); • F indings from animal models often cannot be translated to clinical trials; likewise, modeling of human diseases, especially neuropsy- chiatric disorders, are difficult in animals; • T he lack of standardized biomarker characterization (e.g., elec- troencephalogram, event-related potentials, functional magnetic resonance imaging) is slowing cross-site comparisons and testing of biomarkers; and • A lack of biomarkers that allow for patient stratification, thereby potentially yielding mixed findings in clinical trials. Still, participants expressed enthusiasm that the science is near a tipping point. With coordinated investment in biomarker development, glutamate- related drugs are closer to realization than ever. The key is to advance understanding in the glutamate system and provide opportunities for drug development that have not yet been realized. OPPORTUNITIES Biomarkers hold the key; they are vital to refine targets, provide proof of mechanism, provide proof of concept, and evaluate whether early intervention focused on a single target can prevent or forestall disease. A number of opportunities for advancement were identified over the course of the workshop including the development of disease-specific genetic and epi- genetic biomarkers, the development of new animal models, and the study of small molecules, or metabolomics. Here we highlight three opportunities that emerged as important next steps during discussions. Development of More PET Ligands PET enables non-invasive assessment of molecular activity in humans and animals in vivo. Its premier benefit is to localize and quantify molecular

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35 CHALLENGES AND OPPORTUNITIES events, including signal transduction, gene expression, and protein–protein interactions (Jacobson et al., 2002). With respect to the glutamate synapse and drug development, the foremost application of PET is to show proof of mechanism, particularly by structural target engagement, pharmacokinetics and pharmacodynamics, dose finding, and/or patient stratification. Despite the promise of applying PET-based techniques to the mo- lecular level of the glutamate synapse, PET requires short-lived radioactive ligands that are difficult to synthesize. Many ligands have been developed for acetylcholine, dopamine, and benzodiazepine pathways, but fewer for glutamate pathways. The lag in development, and the importance of find- ing glutamate-related treatments, inspired many participants to emphasize the need for more concentrated efforts on PET ligand development for the glutamate synapse. In discussions among participants, many voiced the need for more radioligands for highly specific glutamate-related proteins at the synapse. One of the most important is to find a PET ligand for ketamine in order to gain more information about its non-competitive binding site within the N-methyl D-aspartate (NMDA) receptor channel, a site currently unidenti- fied. Ketamine has been studied as a treatment for multiple CNS disorders, including depression and pain. The availability of PET ligands to investigate competitive, as well as noncompetitive, NMDA antagonists is also impor- tant, according to Geyer. Participants also encouraged the search for PET ligands for parsing out receptor occupancy, the key feature of a structural biomarker. Other ap- plications of PET, alone or combined with other imaging tools, also could be used to determine drug dosing: the sufficient doses to reach the target and the knowledge that can be gained about a drug’s pharmacokinetics and pharmacodynamics. Another reason to broaden PET ligands is to develop molecular targets that stratify with different types of a particular disease. Most psychiatric disorders, for example, are viewed as a heterogeneous mix of disease subtypes. Because their diagnosis rests on symptoms, as opposed to biomarkers, different diagnostic groupings are unreliable, according to the prevailing wisdom among participants. Misclassification of diagnostic subgroups has serious consequences for drug development. Linking Biomarkers to Disease Endophenotypes For biomarker development, many participants said they prefer to focus research on endophenotypes, which are thought to be the underlying biological basis of a symptom or any other manifestation of disease. They readily lend themselves to biomarker development. In schizophrenia, for example, the endophenotype might be mismatch negativity or prepulse inhi- bition or a combination of the two. It might be genes or gene–gene interac-

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36 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT tions. Endophenotypes are thought to be hereditable and state independent, meaning they manifest in an affected person whether or not the symptom is active. Several workshop participants said they believed biomarkers should be linked to disease endophenotypes and be less contingent on symptom re- porting. Their expectation is that specific endophenotypes might transcend descriptive disease categories and could be found in both schizophrenia and schizoaffective disorder, or in both depression and anxiety. An endopheno- type might even transcend more than two disorders, encompassing as many current disorders as possible that are associated with the same genotypes. Most psychiatric disorders rely on descriptive labels and symptom criteria without regard to etiology or underlying pathophysiology. Research on functional biomarkers and treatments might progress more rapidly if en- dophenotypes are refined. Public–Private Partnerships Workshop participants indicated the potential for significant research progress on many candidate biomarkers for glutamate neurotransmission. But a concerted effort necessary to develop these candidates into valid, reliable, and widespread methods for clinical use has not yet been realized. Many participants expressed the need for collaboration and identified the success of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) as a po- tential model for such an effort. One hallmark of the ADNI effort has been the development of standardizing imaging and fluid biomarker collection across multiple sites. Many participants said that one of the major rate- limiting steps to success in biomarker translation and validation begins with uniformity and standardization of biomarkers across laboratories. For ex- ample, with respect to electrophysiology, the same equipment and ambient sound levels and light conditions would be necessary across laboratories. Development of public–private partnerships offers a potential mechanism for standardization. One problem in developing these partnerships is the different research orientations of academia and industry. Researchers in academia tend not to be focused on drug development. Meanwhile, industry researchers have in the past viewed biomarker development as too remote from giving their company a competitive edge and commercial payoff. Simply put, glutamate- related biomarker development and validation has fallen between the cracks of academic, government, and industry research programs, participants asserted. Meanwhile, new candidate biomarkers can be developed only from large-scale collaborations that combine the resources, technology, and access to human subjects on the scale needed for glutamate biomarker development. Many of the research needs have been previously identified: the lack of PET ligands and biomarkers for patient stratification, among

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37 CHALLENGES AND OPPORTUNITIES others. Lack of translation from animal models to humans has also been an obstacle. In short, there are no organized efforts to take advantage of existing candidate biomarkers or efforts to develop new ones. The lack of a single, validated glutamate biomarker precludes comparisons between a new medication and a benchmark. All of these factors slow progress—prog- ress that could be accelerated with combined efforts. SUMMARY Despite the challenges, participants expressed enthusiasm that glutamate-related drugs will be developed in the near future, especially with coordinated investment in biomarker development. The goal is to advance understanding of the glutamate system and provide new oppor- tunities for drug development. Biomarkers hold the key. They are vital to refining targets, they provide proof of mechanism and concept, and they help researchers to evaluate whether early intervention focused on a single target can prevent or stabilize disease, among other benefits. Glutamate biomarkers may aid in the rational treatments of many dis- eases. This workshop explored the barriers to developing these biomarkers, and identified mechanisms by which those barriers can be overcome. They are only one of many new pieces in the rapidly changing world of scientific advancements to treat disease.

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