SIGNIFICANT STEP FORWARD FOR FIRST CLINICAL TRIAL FOR CHILDREN WITH ADNP SYNDROME
April 1, 2021
ANNOUNCEMENT FOR IMMEDIATE RELEASE
The ADNP Kids Research Foundation is excited to announce that the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai is making rapid progress in advancing the study of ketamine in ADNP Syndrome.
Researchers at the Seaver Autism Center for Research and Treatment at Mount Sinai will start recruiting participants for a new clinical trial scheduled to start in August, to evaluate the safety, tolerability, and efficacy of a low dose of ketamine in chldren with ADNP Syndrome, a rare nuerodevelopmental disorder caused by mutations in the activity dependent neuroprotective protein (ADNP) gene.
The study is led by Dr. Alexander Kolevzon, MD, Professor of Psychiatry and Pediatrics and Clinical Director at the Seaver Autism Center.
ANNOUNCEMENT FOR IMMEDIATE RELEASE
The ADNP Kids Research Foundation is excited to announce that the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai is making rapid progress in advancing the study of ketamine in ADNP Syndrome.
Researchers at the Seaver Autism Center for Research and Treatment at Mount Sinai will start recruiting participants for a new clinical trial scheduled to start in August, to evaluate the safety, tolerability, and efficacy of a low dose of ketamine in chldren with ADNP Syndrome, a rare nuerodevelopmental disorder caused by mutations in the activity dependent neuroprotective protein (ADNP) gene.
The study is led by Dr. Alexander Kolevzon, MD, Professor of Psychiatry and Pediatrics and Clinical Director at the Seaver Autism Center.
Backgrounds and Aims
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare condition but a common genetic form of intellectual disability (ID) and a leading cause for autism spectrum disorder (ASD). Common symptoms also include aberrant behavior, language delays, attention deficit and hyperactivity, sensory seeking, anxiety, and sleep disturbance. Medical features are varied and may include gastrointestinal problems, endocrine and growth problems, hypotonia, gait abnormalities, and visual problems. ADNP syndrome is a haploinsufficiency state due to de novo mutations in the ADNP gene causing loss of function of the ADNP protein. Over 400 genes are regulated by ADNP, which play critical roles in brain formation and other organ development (Mandel et al., 2007). ADNP haploinsufficiency negatively impacts brain formation leading to impaired learning and memory and ADNP+/- mice suffer from learning and memory deficiencies, muscle weakness, and communication problems (Vulih-Shultzman et al., 2007).
The ADNP syndrome clinical phenotype has been described in several publications and several case studies (Helsmoortel et al., 2014; Arnett et al., 2018). The human ADNP gene is approximately 40 kb long and located on the q12 band of chromosome 20 (Zamostiano et al., 2001). The protein is made up of 1,102 amino acids including an 8-amino-acid neuroprotectant peptide referred to as NAP. ADNP is a member of a chromatin remodeling complex, which is also associated with RNA transcription and splicing. ADNP has also been shown to interact with the microtubule (MT) associated protein Tau, leading to dynamic Tau expression and protection against Tau pathology. Tau hyper-phosphorylation has been associated with neurodegeneration and cognitive decline. There is a direct interaction of ADNP with the MT end binding (EB) family of proteins, enhancing Tau-MT binding, where ADNP mutation leads to a disruption in the MT EB protein interaction (Amram et al., 2016; Ivashko-Pachima et al., 2017; Gennet et al., 2008; Oz et al., 2014).
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that disrupts calcium homeostasis in neurons and is widely used in anesthesia. Recently, low-dose ketamine was demonstrated to be efficacious as an adjunctive therapy in adult patients with treatment-resistant depression (Fava et al., 2018; Chen et al., 2019) indicating therapeutic potential beyond conventional use. These findings led to the FDA approval of intranasal esketamine (Spravato®) for treatment-resistant depression.
In pediatric patients, ketamine is reported to have both neuroprotective and neurotoxic effects (Yan et al., 2014). High-dose ketamine is believed to cause neurotoxicity by induction of neuronal apoptosis. However, low-dose ketamine
is extensively used for sedation and analgesia in pediatric patients with an acceptable safety profile (Kurdi et al., 2014).
Several recent studies have examined the mechanistic underpinnings of effects of ketamine on immature brain. Intriguingly, studies in infant rats demonstrated that neurotoxic effects of high-dose ketamine can be prevented by pre-treatment with ADNP in a dose-dependent manner as well as by pretreatment with low-dose ketamine (Turner et al., 2012). Furthermore, in vitro and in vivo treatment with low dose ketamine showed dose-dependent induction of ADNP in rat neurons indicating that neuroprotective effects of low-dose ketamine are, at least in part, mediated by ADNP (Brown et al., 2015). Interestingly, this mechanism also appears to be at play in colon cancer models where ketamine-induced overexpression of ADNP acted as a repressor of WNT signaling, inhibited tumor growth and prolonged survival (Blaj et al., 2017). This result was further corroborated by high expression levels of ADNP In tumor biopsies from patients with colon cancer being associated with better prognosis. Based on the demonstrated ability of low-dose ketamine to induce ADNP overexpression, one can speculate that treatment with low-dose ketamine would have beneficial effect in individuals with ADNP syndrome by compensating for ADNP haploinsufficiency.
The goal of the proposed research is to conduct a Phase 2A, single dose, open-label study to evaluate the safety and tolerability of low-dose ketamine in children with ADNP syndrome.
AIM 1: Evaluate the safety and tolerability of low-dose ketamine in children with ADNP syndrome using physical examination, laboratory-based, and caregiver-based assessments.
AIM 2: Evaluate the efficacy of low-dose ketamine in children with ADNP syndrome targeting core symptoms using the Clinical Global impressions – Improvement Scale and other measures of aberrant behavior, sensory reactivity, sleep, adaptive functioning, and caregiver strain.
AIM 3: Explore the feasibility of objective biological markers in ADNP syndrome using electrophysiological measurement of auditory and visual evoked potentials and computerized eye tracking to assess sensitivity to change with low-dose ketamine treatment and the relationship to clinical outcomes.
AIM 4: Explore the feasibility of blood-based biological markers in ADNP syndrome using RNA and DNA sequencing to measure ADNP expression and methylation profiles in order to assess sensitivity to change with low-dose ketamine treatment and the relationship to clinical outcomes.
At the conclusion of this study, we expect to demonstrate the safety and tolerability of low-dose ketamine in children with ADNP syndrome and anticipate identifying meaningful signals of efficacy in clinical outcome measures to inform future phase 3 studies.
Study Design
The proposed study utilizes a single-dose (0.5 mg/kg), open-label design to investigate the safety, tolerability, and efficacy of treatment with low-dose ketamine in children with ADNP syndrome, ages 5 to 12. Results will inform low-dose ketamine clinical development and the design of future and larger studies in ADNP syndrome (Figure 1).
INSERT HERE
FIGURE 1: Schematic Representation of Study Design. Screening will take place up to four weeks before Baseline. A total of 10 subjects will be recruited and assigned to fixed low-dose ketamine at 0.5 mg/kg.
Study Visits
The study will comprise a:
Study Drug Administration
Ketamine will be administered intravenously (IV) at 0.5 mg/kg over 40 minutes in a single daytime infusion. The drug substance is commercially available and FDA approved as an anesthetic for children in the proposed age range. The principal investigator has received FDA approval to proceed (IND #147201). All preparation and packaging will be performed in the Mount Sinai Research Pharmacy.
Safety Monitoring
Active monitoring throughout the infusion and for two hours thereafter will ensure safety and tolerability. Tolerability will then be assessed by the research physician throughout the study.
Risks Associated with Ketamine
Ketamine is a sedative/analgesic and general anesthetic for human use. It may produce mild to moderate increases in blood pressure, heart rate, and cardiac output. Other potential side effects include sedation, headache, nausea, and restlessness. Because ketamine is administered intravenously, there is a risk of pain and irritation at the IV site. In addition, there is a risk of ketamine-induced perceptual disturbances that may manifest as vivid dreaming, visualization of psychedelic color, suspension in space, kaleidoscopic floating, and out-of-body experiences. Some patients describe these psychic experiences as bizarre or frightening. Overall, however, ketamine has a favorable acute safety profile. Over the past several decades, ketamine has been administered as an anesthetic to several million adults and children.
Study Population
INCLUSION CRITERIA:
1. Is 5 to 12 years old (inclusive) at the time of informed consent;
2. Has a diagnosis of ADNP syndrome, confirmed by genetic testing prior to subject randomization;
3. Has a Clinical Global Impression-Severity score of 4 (moderately ill) or greater at screening;
4. Any concomitant medication, including anti-epileptic and/or behavioral medications, supplements, and special diets, must be at a stable dose for at least 4 weeks before;
5. Has an English-speaking caregiver capable of providing informed consent and able to attend all scheduled study visits, oversee the administration of study drug, and provide feedback regarding the subject’s behavior and other symptoms as described in the protocol;
6. Provide assent to the protocol if appropriate;
7. Has a caregiver who will agree not to post any of the subject’s personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook and Twitter) until they have been notified that the study is completed.
8. Age-specific blood pressure parameters for inclusion in the study will be based on established guidelines.
Activity-dependent neuroprotective protein (ADNP) syndrome is a rare condition but a common genetic form of intellectual disability (ID) and a leading cause for autism spectrum disorder (ASD). Common symptoms also include aberrant behavior, language delays, attention deficit and hyperactivity, sensory seeking, anxiety, and sleep disturbance. Medical features are varied and may include gastrointestinal problems, endocrine and growth problems, hypotonia, gait abnormalities, and visual problems. ADNP syndrome is a haploinsufficiency state due to de novo mutations in the ADNP gene causing loss of function of the ADNP protein. Over 400 genes are regulated by ADNP, which play critical roles in brain formation and other organ development (Mandel et al., 2007). ADNP haploinsufficiency negatively impacts brain formation leading to impaired learning and memory and ADNP+/- mice suffer from learning and memory deficiencies, muscle weakness, and communication problems (Vulih-Shultzman et al., 2007).
The ADNP syndrome clinical phenotype has been described in several publications and several case studies (Helsmoortel et al., 2014; Arnett et al., 2018). The human ADNP gene is approximately 40 kb long and located on the q12 band of chromosome 20 (Zamostiano et al., 2001). The protein is made up of 1,102 amino acids including an 8-amino-acid neuroprotectant peptide referred to as NAP. ADNP is a member of a chromatin remodeling complex, which is also associated with RNA transcription and splicing. ADNP has also been shown to interact with the microtubule (MT) associated protein Tau, leading to dynamic Tau expression and protection against Tau pathology. Tau hyper-phosphorylation has been associated with neurodegeneration and cognitive decline. There is a direct interaction of ADNP with the MT end binding (EB) family of proteins, enhancing Tau-MT binding, where ADNP mutation leads to a disruption in the MT EB protein interaction (Amram et al., 2016; Ivashko-Pachima et al., 2017; Gennet et al., 2008; Oz et al., 2014).
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that disrupts calcium homeostasis in neurons and is widely used in anesthesia. Recently, low-dose ketamine was demonstrated to be efficacious as an adjunctive therapy in adult patients with treatment-resistant depression (Fava et al., 2018; Chen et al., 2019) indicating therapeutic potential beyond conventional use. These findings led to the FDA approval of intranasal esketamine (Spravato®) for treatment-resistant depression.
In pediatric patients, ketamine is reported to have both neuroprotective and neurotoxic effects (Yan et al., 2014). High-dose ketamine is believed to cause neurotoxicity by induction of neuronal apoptosis. However, low-dose ketamine
is extensively used for sedation and analgesia in pediatric patients with an acceptable safety profile (Kurdi et al., 2014).
Several recent studies have examined the mechanistic underpinnings of effects of ketamine on immature brain. Intriguingly, studies in infant rats demonstrated that neurotoxic effects of high-dose ketamine can be prevented by pre-treatment with ADNP in a dose-dependent manner as well as by pretreatment with low-dose ketamine (Turner et al., 2012). Furthermore, in vitro and in vivo treatment with low dose ketamine showed dose-dependent induction of ADNP in rat neurons indicating that neuroprotective effects of low-dose ketamine are, at least in part, mediated by ADNP (Brown et al., 2015). Interestingly, this mechanism also appears to be at play in colon cancer models where ketamine-induced overexpression of ADNP acted as a repressor of WNT signaling, inhibited tumor growth and prolonged survival (Blaj et al., 2017). This result was further corroborated by high expression levels of ADNP In tumor biopsies from patients with colon cancer being associated with better prognosis. Based on the demonstrated ability of low-dose ketamine to induce ADNP overexpression, one can speculate that treatment with low-dose ketamine would have beneficial effect in individuals with ADNP syndrome by compensating for ADNP haploinsufficiency.
The goal of the proposed research is to conduct a Phase 2A, single dose, open-label study to evaluate the safety and tolerability of low-dose ketamine in children with ADNP syndrome.
AIM 1: Evaluate the safety and tolerability of low-dose ketamine in children with ADNP syndrome using physical examination, laboratory-based, and caregiver-based assessments.
AIM 2: Evaluate the efficacy of low-dose ketamine in children with ADNP syndrome targeting core symptoms using the Clinical Global impressions – Improvement Scale and other measures of aberrant behavior, sensory reactivity, sleep, adaptive functioning, and caregiver strain.
AIM 3: Explore the feasibility of objective biological markers in ADNP syndrome using electrophysiological measurement of auditory and visual evoked potentials and computerized eye tracking to assess sensitivity to change with low-dose ketamine treatment and the relationship to clinical outcomes.
AIM 4: Explore the feasibility of blood-based biological markers in ADNP syndrome using RNA and DNA sequencing to measure ADNP expression and methylation profiles in order to assess sensitivity to change with low-dose ketamine treatment and the relationship to clinical outcomes.
At the conclusion of this study, we expect to demonstrate the safety and tolerability of low-dose ketamine in children with ADNP syndrome and anticipate identifying meaningful signals of efficacy in clinical outcome measures to inform future phase 3 studies.
Study Design
The proposed study utilizes a single-dose (0.5 mg/kg), open-label design to investigate the safety, tolerability, and efficacy of treatment with low-dose ketamine in children with ADNP syndrome, ages 5 to 12. Results will inform low-dose ketamine clinical development and the design of future and larger studies in ADNP syndrome (Figure 1).
INSERT HERE
FIGURE 1: Schematic Representation of Study Design. Screening will take place up to four weeks before Baseline. A total of 10 subjects will be recruited and assigned to fixed low-dose ketamine at 0.5 mg/kg.
Study Visits
The study will comprise a:
- Screening period which will take place within the 4 weeks preceding a Baseline visit;
- Baseline visit on day 0 for baseline assessments and administration of study drug;
- Clinic visits for safety and efficacy assessments at weeks Day 1, week 1, 2, and 4. Safety information will be collected at all clinic visits.
Study Drug Administration
Ketamine will be administered intravenously (IV) at 0.5 mg/kg over 40 minutes in a single daytime infusion. The drug substance is commercially available and FDA approved as an anesthetic for children in the proposed age range. The principal investigator has received FDA approval to proceed (IND #147201). All preparation and packaging will be performed in the Mount Sinai Research Pharmacy.
Safety Monitoring
Active monitoring throughout the infusion and for two hours thereafter will ensure safety and tolerability. Tolerability will then be assessed by the research physician throughout the study.
Risks Associated with Ketamine
Ketamine is a sedative/analgesic and general anesthetic for human use. It may produce mild to moderate increases in blood pressure, heart rate, and cardiac output. Other potential side effects include sedation, headache, nausea, and restlessness. Because ketamine is administered intravenously, there is a risk of pain and irritation at the IV site. In addition, there is a risk of ketamine-induced perceptual disturbances that may manifest as vivid dreaming, visualization of psychedelic color, suspension in space, kaleidoscopic floating, and out-of-body experiences. Some patients describe these psychic experiences as bizarre or frightening. Overall, however, ketamine has a favorable acute safety profile. Over the past several decades, ketamine has been administered as an anesthetic to several million adults and children.
Study Population
INCLUSION CRITERIA:
1. Is 5 to 12 years old (inclusive) at the time of informed consent;
2. Has a diagnosis of ADNP syndrome, confirmed by genetic testing prior to subject randomization;
3. Has a Clinical Global Impression-Severity score of 4 (moderately ill) or greater at screening;
4. Any concomitant medication, including anti-epileptic and/or behavioral medications, supplements, and special diets, must be at a stable dose for at least 4 weeks before;
5. Has an English-speaking caregiver capable of providing informed consent and able to attend all scheduled study visits, oversee the administration of study drug, and provide feedback regarding the subject’s behavior and other symptoms as described in the protocol;
6. Provide assent to the protocol if appropriate;
7. Has a caregiver who will agree not to post any of the subject’s personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook and Twitter) until they have been notified that the study is completed.
8. Age-specific blood pressure parameters for inclusion in the study will be based on established guidelines.
If you are interested in information and future participation on this and other studies, please fill out the contact information form on our RESEARCH page.
Forward Looking Statements
Statements contained herein, other than those which are strictly statements of historical fact may include forward looking information. Such statements will typically contain words such as "believes", "may", "plans", "will", "estimate", "continue", "anticipates", "intends", "expects", and similar expressions. While forward-looking statements represent management's outlook based on assumptions that management believes are reasonable, forward-looking statements by their nature are subject to known and unknown risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from any future results, events or developments expressed or implied by them.
Forward Looking Statements
Statements contained herein, other than those which are strictly statements of historical fact may include forward looking information. Such statements will typically contain words such as "believes", "may", "plans", "will", "estimate", "continue", "anticipates", "intends", "expects", and similar expressions. While forward-looking statements represent management's outlook based on assumptions that management believes are reasonable, forward-looking statements by their nature are subject to known and unknown risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from any future results, events or developments expressed or implied by them.
