Genetics research is a rapidly growing enterprise within the field of medicine, particularly in neurology and neuroscience. As scientists learn more about the genetic components of neurological diseases, a new class of therapies consisting of compounds designed to target specific pathways will likely have a significant impact for patients.

One of these agents is NFC-1, a non-stimulant metabotropic glutamate receptor (mGluR) neuromodulator that is currently entering Phase 2/3 development for the treatment of mGluR network mutation positive ADHD, as well as symptoms resulting from 22q11.2 Deletion Syndrome (22q11.2DS)—a rare neurogenetic disorder that affects adolescents and leads to a wide range of medical, psychiatric, and behavioral abnormalities. Initial results show improvements in multiple neuro-behavioral symptoms, including inattention, hyperactivity, anxiety, and mood. Ahead, experts involved in research of NFC-1 for both pediatric ADHD and 22q11.2 DS share insights on how this agent may shape the therapeutic landscape.

A Q&A with Josephine Elia, MD

How would you characterize the current moment in ADHD research and treatment?

Attention Deficit Hyperactivity Disorder (ADHD) is a complex condition from a neurological perspective. According to Dr. Elia, ADHD is too nuanced to be reduced to a simple diagnosis. “ADHD is a combination of characteristics that include activity level, impulsivity, and executive functions. These characteristics are on a continuum similar to blood pressure or blood sugar and can cause impairment when they are at the extremes of the continuum (too little or too much),” says Dr. Elia. “Whereas in the past many of these aspects were analyzed or treated in clusters, we are now beginning to look at them separately,” Dr. Elia explains. This approach appears to be taking hold both clinically as well as in research, she observes.

Can you discuss challenges and new approaches in management of ADHD?

“As far as treatments go, we really have not had many advances in recent years,” says Dr. Elia. “The hallmark medicines that have been in use for decades, such as methylphenidate and amphetamines, are still the most effective medicines out there. These drugs have been used to treat ADHD since the 1930s and in the past two decades they have been repackaged using novel delivery mechanisms that provide longer-term availability.” In terms of why they have been so effective, Dr. Elia notes we do not yet know how these medications work. “In the past it was thought that they inhibited dopamine reuptake, however animal models where the dopamine transporter was knocked out manifested similar effects,” she explains. Recent genetic studies are also indicating that ADHD is not due to a single or a few genes but rather many (e.g., hundreds or thousands) rare variants, impacting genes in numerous neuronal pathways. According to Dr. Elia, this may explain the high response rate consistently reported for these medications. “Further support comes from epigenetic studies that are showing that these medications change gene expression in hundreds of genes throughout the brain.”

More recently, the development of noradrenergic agents and alpha-agonists has given an alternative to more traditional approaches. However, Dr. Elia notes that their efficacy is limited, with roughly a 20 percent response rate. Nevertheless, these agents may offer a glimpse at the growing role of genetics in the future of treatment of neuropsychiatric conditions. “Hopefully someday we can get hold of genome sequencing and look at different areas of the brain. We might be ably to identify patients that have a genetic variant that is implicated in the pathway of these agents,” says Dr. Elia.

What is the role of genetics in current research and how may it eventually figure into treatments for ADHD?

“Back in 2003, we received a grant from the National Institutes of Health to recruit a cohort of 500 patients and their parents with the goal of identifying genes that caused ADHD. We didn’t find any single genes of significance,” says Dr. Elia. “Luckily the technology was advancing and allowed us to search at the genomic level and in larger sample sizes. When we combined our dataset with another 3,000 ADHD patients and 12,000 healthy control subjects, we found that about 10 percent of our sample had structural genetic variants (segments of the genome had duplications or deletions) in areas that contain genes that directly or indirectly disrupt the glutamatergic neuronal pathways.” According to Dr. Elia, this was an important discovery since it identified glutamatergic impairment in the etiology of ADHD.1

Can you talk about NFC-1 and the role it could eventually play in treatment?

The significance of the role for the glutamatergic impairment in ADHD is now leading researchers to identify and test novel treatments. One of these agents currently being developed is NFC-1, a glutamatergic activator derived from the amino acid, glutamic acid. “We were able to identify a cohort of adolescents that have genetic variations along the genome that disrupted the glutamatergic pathway and treat it with the NFC-1 medicine,” says Dr. Elia. “We obtained FDA approval to enroll a small cohort of 30 adolescents, first in a Phase 1 pharmacokinetic study that assessed safety followed by a five-week Phase 1b dose-escalation study.

Results from this open, non-controlled study demonstrated significant efficacy signals in several validated ADHD scales in this targeted population of ADHD adolescents with rare genetic variants impacting on the glutamatergic neuronal pathways. Additionally, the treatment effect of NFC-1 appeared more robust over time and at higher doses. NFC-1 was well tolerated, with no treatment-related serious adverse events reported. Additionally, one half of the sample elected to continue in a long-term safety trial in order to maintain access to therapy.

While these results are preliminary, they are nonetheless encouraging. Moreover, according to Dr. Elia, these findings could have implications for the larger neuropsychiatric spectrum, given that the study subjects with comorbid mood and anxiety also showed improvement. “This is extremely important, given that approximately one-quarter of kids with ADHD have some anxiety or mood disorders,” she explains.

What are the next steps for this drug? How do you expect the broader spectrum of therapy for neuropsychiatric conditions to take shape in coming years?

Within the context of depression and mood disorders in children, the development of NFC-1 offers hope for a brighter future. “We currently have very little to offer these patients, and the currently available medications provide minimal impact.” Nevertheless, though the results of the NFC-1 trials are encouraging and warrant further investigation, “we still have a long, long way to go,” Dr. Elia explains.

In terms of next steps for NFC-1, Dr. Elia notes that a yearlong extension study is ongoing for the treatment of ADHD. Additionally, studies are being planned for NFC-1 in patients with 22q11.2 Deletion Syndrome (see page 38). Larger trials in patients with ADHD are also being planned.

As efforts continue to investigate the effects of NFC-1, it is important to consider the broader perspective regarding the continued evolution of genomic research in neurological disease. “One of the goals of treating kids is to prevent progression of symptoms to more serious disorders later on,” Dr. Elia explains. Thus, early intervention could open up a host of opportunities. “For example, if we treat symptoms of ADHD early on, can we stop progressions of more serious developments later on during development? If we treat the anxiety, will we prevent progression to depression?”

Dr. Elia is hopeful that as investigations into NFC-1 progresses, it may enable scientists and clinicians to learn more about treating and potentially preventing symptoms of neuropsychiatric conditions. n

Josephine Elia, MD Is a Psychiatrist at the Division of Pediatric Behavioral Health at Nemours Children’s Health System in Wilmington, DE.

1. Elia J, et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet. 2011 Dec 4;44(1):78-84.

A Q&A with Donna M. McDonald-McGinn, MS, LCGC

What is 22q11.2 Deletion Syndrome what role does it play in neurological conditions?

According to Professor McDonald-McGinn, 22q11.2 Deletion Syndrome (22q11.2DS) has had a number of previous clinical names dating back several decades. “In the mid-1960s, Dr. Angelo DiGeorge, an endocrinologist, described an association between hypoparathyroidism and immunodeficiency. Later, congenital heart disease was added, leading to the associated triad now known as DiGeorge syndrome (DGS),” notes Professor McDonald-McGinn. “Then, in the early 1980s, Dr. Elaine Zackai at Children’s Hospital of Philadelphia (CHOP) evaluated a child with features of DGS who also had cleft palate and an intestinal abnormality. Chromosome studies in the laboratory of Dr. Beverly Emanuel at CHOP identified an unbalanced 10:22 rearrangement resulting in loss of a piece of chromosome 10 and 22. Thereafter, additional patients came to attention with DGS and other unbalanced chromosomal rearrangements that involved chromosome 22,” she observes. Thus, the conclusion was drawn that DGS was due in part to a 22q11.2 deletion. According to Professor McDonald-McGinn, Dr. Emanuel later found that about 25 percent of patients with DGS had a visible deletion of chromosome 22 that could be visualized under a microscope. “Then, in the 1990s, a new technique known as FISH studies for the 22q11.2 deletion conducted both at CHOP in Dr. Emanuel’s lab and in the lab of Dr. Peter Scambler in the UK, led to the understanding that almost all of patients with DGS had a 22q11.2 deletion. Shortly thereafter, it became apparent that other clinically related conditions (VCFS and CTAF) also had a 22q11.2 deletion,” she explains.

“Clinicians were describing these conditions in separate settings, but now we know that most individuals with these clinical diagnoses actually have 22q11.2 DS and are missing roughly 50 genes,” says Professor McDonald-McGinn. “One gene, in particular (TBX1), has been linked to congenital heart disease.” She also observes that there has been vast research surrounding this condition and the link to neuropsychiatric phenotypes. “In fact, there is an elevated prevalence of cognitive deficits, speech and language delay, autism spectrum disorder, ADHD, and anxiety. Moreover, 25 percent of individuals with 22q11.2DS will develop psychosis, specifically schizophrenia,” says Professor McDonald-McGinn. “These discoveries have brought this condition to the forefront for everyone working on brain and behavior.”

Currently, multiple research studies are underway examining patients with 22q11.2DS and the potential role of genes within the deletion in the development of behavioral phenotypes such as ADHD, autism, anxiety, and psychosis. Moreover, continued investigations, including the introduction of clinical trials, will ultimately elucidate the utility of precision medicine (such as with the investigational agent NFC-1, for example) for this and other related conditions, according to Professor McDonald-McGinn.

How is current and future research addressing the effects of the 22q11.2 Deletion Syndrome?

“The aim of current research studies is to identify genotype-phenotype correlations in patients with the 22q11.2DS, specifically to understand the etiology of associated neuropsychiatric conditions with the ultimate eye towards better treatment strategies,” Professor McDonald-McGinn notes. “In the big picture, what matters most is ameliorating the patient’s symptoms,” she explains, “whether they be associated with 22q11.2DS or more broadly applicable to the general population.

As research into 22q11.2DS expands, Professor McDonald-McGinn is hopeful that new advancements will allow researchers and clinicians to identify at-risk individuals earlier and develop more successful interventions. For example, she notes, “Approximately 15 percent of individuals with this condition develop idiopathic seizures, so it is possible that further research will reveal potential ‘seizure genes’.” There is a broader upside of this research, as well, she observes. “We are hopeful that in the future we will have insights into who is at ‘low-risk,’ versus ‘high-risk,’ and more importantly we will have better options for behavioral and medical remediation.”


How would you describe the role of genetics in the evolving research and treatment spectrum for neurological diseases?

“We are on the cusp of a scientific revolution,” says Professor McDonald-McGinn. “From a research standpoint, we are churning at a pace that is lightning fast. We see it in every direction across many fields, filtering down to prenatal screening for treatable disease. By the same token, it is important to exercise extreme caution at every step. We need to be very judicious in setting up protocols and designing trials,” she observes. “It is better to have fewer numbers and do studies absolutely correctly, especially in medically fragile populations, as safety must always be the number one priority.”

In the broader scope, Professor McDonald-McGinn sees the recent innovations regarding genomic research and neuropsychiatric conditions as representing a major step in understanding these diseases and how they are treated. “We now have international consortia working together in investigating these areas,” she says. “It is not without challenges, but the hope is that the benefits to the patients will be pronounced—which is definitely the collective goal.” n

Donna M. McDonald-McGinn, MS, LCGC, is a Clinical Professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania. She is also Director of the 22q and You Center, Associate Director of the Clinical Genetics Center, and Chief of the Section of Genetic Counseling at Children’s Hospital of Philadelphia.