GenomeWeb – For many years, researchers specializing in neurodevelopmental disorders have been searching for the genetic causes underlying conditions such as attention deficit hyperactivity disorder (ADHD). But such neuropsychiatric disorders have been hard to pin down — genes that are thought to be at least partially responsible for causing them have been discovered over the years, but so far, the research hasn't advanced far enough to be useful in creating new treatments for patients.
But at the Nemours/Alfred I. DuPont Hospital for Children, psychiatric researcher Josephine Elia is trying to change that. Elia, her colleagues at The Children's Hospital of Philadelphia (CHOP), and their collaborators across the US recently conducted a study of more than 1,000 children with ADHD and found evidence to suggest that mutations in the glutamatergic gene network may underlie about 20 percent of ADHD cases. Further, the study results bolster a Phase 2/3 trial of a new treatment for ADHD that, if approved, would be the first targeted therapy for the condition.
The latest work by Elia and her colleagues builds on a progression of studies they've conducted, starting in 2010 and 2011. In a study published in Molecular Psychiatry in 2010, Elia, Hakon Hakonarson, and other colleagues at CHOP and the University of Pennsylvania searched for copy number variations in 335 ADHD patients and their parents.
"Our group was looking for single genes for these neuropsychiatric disorders, but that's not what we found," Elia told GenomeWeb. "What we found was that there most likely might a few single genes, but really for most patients with ADHD, it's not due to a single gene."
In a Nature Genetics paper in 2011, the researchers looked at 2,493 patients with ADHD and 9,222 controls, and found that there were sections of non-coding DNA that were either duplicated or deleted in regions that affected the glutamatergic system, one of the major neuronal pathways.
CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts, including deletions in GRM5, GRM7, and GRM8, and duplications in GRM1. "A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in about 10 percent of the cases. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts," the authors wrote.
Prior to this study, Elia told GenomeWeb, "the main pathway that was thought to be involved [in ADHD] was dopamine and the dopaminergic pathway, and all the drugs that we have supposedly impact on that. So we were very surprised to find [these mutations]. This was the first time there was any major evidence implicating the glutamatergic system."
Importantly, Elia added, the researchers were able to replicate their results by looking at cohorts of ADHD patients from across the world. What they saw convinced them that they had found a true signal.
The current study, which is still ongoing, also seems to confirm these results. In a poster presentation at the recent American Academy of Child and Adolescent Psychiatry annual meeting in New York, Elia showed some of the experimental data that the researchers have collected so far.
Using Illumina genotyping assays, they tested saliva samples collected from 1,013 children with ADHD, ages six to 17, from 23 sites across the US. Around 22 percent — 220 kids — were found to have mutations in GRM network genes. When broken down into smaller groups by age, the researchers found mutations in 26 percent of the children who were six to 12 years old, and in 20 percent of the children who were 12 to 17 years old.
"That may not sound like a big number, but when you think of how many kids and adults have ADHD, then 20 percent is a huge number," Elia said. "And we really don't have any current treatments that impact on these pathways…. We'll see once we recruit another thousand whether it ends at 20 percent."
The results also suggested that about 70 percent of the mutations involved 15 genes, but the researchers believe that they will eventually find mutations in all 273 genes in the GRM network. The team is currently in the process of recruiting 1,000 more children, and plans to continue the study and gather more data.
It's possible that this GRM mutation signature could signal an ADHD subset, Elia said. The poster noted that interviews with parents of the children indicated that mutation-positive and mutation-negative patients were clinically similar, but that anger control and disruptive behaviors appeared to be of greater concern in the mutation-positive patients.
The team is also working with genomic medicine company Medgenics — which sponsored this new study — to test a targeted therapy for ADHD. The therapy, dubbed NFC-1, is being tested in a randomized, double-blind, placebo-controlled, parallel-group Phase 2/3 study versus placebo in adolescent patients with ADHD who have genetic mutations impacting the glutamatergic network. Children in Elia's study who were found to have GRM gene mutations are being recruited into the drug study as well.
In the Phase 1 safety study conducted on NFC-1, the researchers also saw a drug effect, Elia noted, which suggested that continuing trials could bear fruit. The current phase of testing could be completed sometime in 2017, she added.
"It's definitely the first [treatment] that targets the population that has the genomics variations, and it's also the first that will even target the glutamatergic pathway malfunction," Elia said. "The current drugs we have — the Ritalin, the Adderall, and so on — we don't truly know how those drugs work. We have hypotheses, and they may have some glutamatergic activity, but that's not their predominant effect. So this will be a drug that truly modulates that system."
Elia also noted that there could be potential for a diagnostic at some point in the future that would differentiate this ADHD patient population from others, which would also help target the children who would benefit the most from this particular therapy.
"In our preliminary study, it was the kids who had the strongest signals that did the best [on the drug], so yes, in the long run we're going to be identifying the best match for the disease and treatment, because that will in many ways decrease the potential side effects or also the response rates," Elia said.
Importantly, this may signal a shift in the treatment paradigm for ADHD and, perhaps, related conditions as well. "If 20 percent of the ADHD population has variations in the glutamatergic pathway, then probably other subgroups will get identified," Elia said. And identifications of certain subgroups could lead not only to new therapies, but also to more targeted applications of the treatments that already exist.