The DNAP/ketamine trial was the first clinical study generated by information gleaned from the Precision Medicine Institute’s artificial intelligence tool.
Information gathered via artificial intelligence has opened the door to a possible treatment for a rare genetic neurodevelopmental disorder. Results published in Human Genetics and Genomic Advances suggest that low-dose ketamine is generally safe, well tolerated, and effective in treating clinical symptoms in children diagnosed with activity-dependent neuroprotective protein syndrome, a disorder derived from a mutation in the DNAP gene.
Low-dose ketamine has been identified as a possible therapeutic target for ADNP syndrome by the Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham. This information has been forwarded to the ADNP Kids Research Foundation, the leading national advocate for ADNP Syndrome research. This organization contacted investigators from the Seaver Autism Center for Research and Treatment at Mount Sinai Hospital, who conducted a clinical trial and published their findings online on August 27.
The impetus to investigate ketamine, an FDA-approved drug used in anesthesia, pain management and depression, came from an artificial intelligence tool called mediKanren. Matt Might, Ph.D., director of the UAB Precision Medicine Institute, is a computer scientist by training who became an expert in precision medicine after the birth of his son with a rare genetic disease. He developed mediKanren with funding from the National Center for Advancing Translational Sciences.
Might and his team brought global medical literature into mediKanren. It then used artificial intelligence reasoning to make inferences. Simply put, if presented with as much information as possible about a disease or condition, it will sift through the literature for potential findings.
“We had a surgical resident at UAB whose son had ADNP syndrome,” Might said. “I was also in contact with Sandra Sermone, the founder of the ADNP Kids Research Foundation, which now has a register of 250 children with the syndrome. We were able to present mediKanren with enough information about ADNP to solicit a response. And the answer was ketamine.
According to the National Institutes of Health, ADNP syndrome is a complex neurodevelopmental disorder that affects the brain and many other areas and functions of the body. ADNP syndrome can affect muscle tone, eating, growth, hearing, vision, sleep, and fine and gross motor skills, as well as the immune system, heart, endocrine system, and gastrointestinal tract . ADNP syndrome causes behavioral disorders such as autism spectrum disorders.
The use of ketamine in the United States has been approved since 1970. Sermone, whose son was the first person in the United States diagnosed with ADNP syndrome, began to spread in scientific studies reported by mediKanren.
“In several studies using animal models, researchers have reported that ketamine appeared to stimulate DNAP production in brain cells,” Sermone said. “Children born with ADNP syndrome have a healthy copy of the ADNP gene and a broken copy. The healthy copy produces the DNAP protein, essential for proper neurological development, unlike the broken copy. As a result, the child does not receive enough DNAP protein for normal development.
Sermone presented the evidence she found to investigators at Mount Sinai, a leading institution in ADNP syndrome research, which launched the clinical trial in 2020.
“We were intrigued by the preclinical evidence suggesting that low-dose ketamine can increase ADNP protein levels and compensate for its loss in ADNP syndrome, so we designed this study to assess safety, tolerability and outcomes. effects of low-dose ketamine in children with the syndrome,” said Alexander Kolevzon, MD, clinical director of the Seaver Autism Center. “We also sought to explore the feasibility of using electrophysiological biomarkers and eye tracking computerized to assess treatment sensitivity.”
Using parental report instruments to assess treatment effects, ketamine has been associated with improvements in a wide range of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors and sensory sensitivities, one week after administration.
Clinician-rated assessment results indicated improvement based on the Clinical Global Impression-Improvement Scale, a 7-point scale commonly used by clinicians to assess how much a patient’s disease has improved or worsened compared to a baseline state at the start of an intervention. . Importantly, the results of assessments assessed by clinicians and caregivers were largely consistent. The results also highlight the potential for assessing early changes in social attention with computerized eye tracking and electrophysiological measurement of a listening task known as the steady-state auditory response.
“We are encouraged by these findings, which provide preliminary support for ketamine to help reduce the negative effects of this devastating syndrome,” Kolevzon said. “Future studies using a placebo-controlled design and investigating the effects of repeated doses over a longer duration and in a larger cohort of participants are needed before ketamine is used in the clinic, but our study is a promising first step. in this process.”
“If these early results are validated, we would have a drug already approved by the FDA that could reverse the condition in very young children and potentially benefit older children as well,” Sermone said. “We could be on the verge of an incredible breakthrough for this condition. We need more families with ADNP syndrome to come forward and, more importantly, we need more resources to fund the next stage of research.
Might believes this is the first time an AI tool has led directly to a clinical trial.
“This is the first time anyone has amassed enough evidence starting with our recommendations to go to the FDA to get permission to start a study,” Might said. “This is the kind of progress we hope to achieve every day through the Precision Medicine Institute. These results are incredibly exciting, and we are proud of the small role we played in bringing this discovery to families with ADNP syndrome.