1.
Vasopressin 1a Antagonist for Social Cognition in Autism
This is a clinical study of a drug called RO5028442 for the study of
Autistic Disorder. Individuals with Autistic Disorder are defined by the DSM-IV
as having difficulties with social interaction and communication, and
presenting with repetitive behaviors. Many individuals with Autistic
Disorder may also have associated symptoms such as irritability, aggression,
and self-injury. The study will also help to see if the new drug is safe,
tolerable and effective in reducing the symptoms of autism.
The study aims to:
● Explore the effects of a single dose of RO5028442 in adult high
functioning autistic patients of exploratory biomarkers (ex. eye-tracking) of
core deficits of the disorder
● Assess the safety and tolerability of a single
dose of RO5028442 in adult
high-functioning autistic patients
● Explore the correlation between AVPR1A
polymorphisms and response to RO5028442 in high functioning autistic patients.
In other words, we will explore whether or not certain genetic characteristics
will predict patient response to the study drug, RO5028442.
Background
The study drug RO5028442 is a potent and highly selective antagonist of
the human vasopressin type 1a (V1a) receptor. Vasopressin is thought to have a
profound influence on higher brain functions such as emotional control and
social behavior, or, the behaviors that comprise the associated symptoms of
autism spectrum disorders. In non-human animals, vasopressin has been
implicated in male typical social behaviors such as pair-bond formation and
courtship, and vasopressin was also found to affect social recognition and
interaction in rodents via its modulatory effect on olfaction (a sensory
modality that may also be impaired in autism spectrum disorders).
Importance
Currently, there exists no reliable pharmacological treatment that
selectively addresses behavioral problems for autism spectrum disorders. In
addition, there is a dire need for intervention that can help clinical
populations with associated behavioral disturbances of autism. This study is
important in proving the efficacy, in a large-scale clinical trial, of a novel
approach to threat the core deficits of autism spectrum disorders
If you or your child are interested
in participating in this study, please contact Tara Kahn at (718) 653-4859 x226
or tkahn@montefiore.org
2. Milcanipran (Norepinephrine Reuptake Inhibitor) for Autism
Autism Spectrum Disorders (ASD) include Autistic disorder, Asperger's
syndrome and Pervasive Developmental Disorder Not Otherwise Specified
(PDD-NOS). These are developmental disorders beginning prior to three years of
age. There are three core symptom domains of ASD, including social deficits,
repetitive behaviors and language deficits. Patients can also have
associated symptoms of attentional deficits, disruptive behaviors and
intellectual disability. There is currently no FDA approved treatment for
the core symptoms of autism.
Focussing on the underlying brain circuitry of autism, we are
interested in the relationship of the locus-coeruleus/noradrenergic (LC-NA)
system and dramatic fluctuations in behavioral states in autism. Specifically,
we are interested in observing how intrinsic and environmental stressors acting
upon a substrate of genetic and epigenetic variations during a protracted
maturational window of vulnerability developmentally dysregulate the LC-NA
system. Dysregulation of the LC-NA system may be associated with compulsive
behaviors and an absence in inhibition, as found in ADHD or symptoms of autism
spectrum disorders.
The drug Milnacipran is said to play a role in the activation and
normalization of certain brain circuits (the locus-coeruleus-noradrenergic
system). If the LC-NA has been functionally deactivated at an early stage of
development, as research suggests, it may be capable of being restored with a
norepinephrione reuptake inhibitor such as Milnacipran. In this study, then, we
use Milnacipran to regulate LC-NA system function and improve symptoms of
autism such as attention, irritability, repetitive behaviors and social
cognition.
In this study, we hope to:
1. Determine whether Milnacipran improves attention dysfunction in
patients with autism
2. Determine whether milnacipran improves irritability, repetitive behaviors
and social cognition in patients with autism
3. Determine whether Milnacipran normalizes motor impulsivity brain
circuitry (right inferior frontal to subcortical circuirty) on functional MRI
in response to the Motor Inhibition NoGo-Go Task
If you or your child are interested
in participating in this study, please contact Tara Kahn at (718) 653-4859 x226
or tkahn@montefiore.org
3. An fMRI and Epigenomics Study in Adult Autism: Response to Intranasal Oxytocin and Placebo
Oxytocin, a
nine-amino-acid peptide, is widely distributed throughout the peripheral and
central nervous systems and has been found to affect affiliative behaviors,
including sexual behavior, mother-infant and adult-adult pair-bond formation,
separation distress, and other aspects of social attachment. Further, oxytocin
has been shown to affect behaviors that show a striking similarity to the
symptoms of autism; namely, oxytocin affects the expression of repetitive
behaviors, stress reactivity and the regulation of affiliative behaviors. From
these findings and preliminary findings from Dr. Hollander’s research, it is
believed that oxytocin may be involved in the etiology of autism, and may be a
valuable tool for the treatment of autism spectrum disorders. In this study, we
seek to explore safety and therapeutic efficacy of intranasal oxytocin in
treating repetitive behaviors and social functioning/cognitive deficits in
adults with autism spectrum disorders.
Evidence is
emerging that the three symptom domains of autism (i.e., the core domains of
deficits in social functioning; deficits in expressive and receptive language
and non-verbal communication; and repetitive behaviors and restricted
interests) are expressed through discrete neuropathological brain circuits. In
addition to treatment with intranasal oxytocin, we also administer fMRI and
cognitive activation paradigms to explore the neural activation patterns of the
social and repetitive behavior domains in subjects with autism and the
mediating effect of oxytocin on such circuits.
In addition to
oxytocin treatment and fMRI analysis, this study uses epigenetic findings to
illuminate the underlying endophenotype of autism. We examine the oxytocin
receptor gene (OXTR) which has recently been associated with hypermyelination
of the gene promoter, and a reduction in mRNA expression. Epigenetic regulation
of OXTR may be an important factor in the development of the disorder, and may
potentially be helpful in predicting response to oxytocin treatment, and as a
moderator of oxytocin treatment response.
If you or your child are interested in participating in this study,
please contact Tara Kahn at (718) 653-4859 x226 or tkahn@montefiore.org
4.
Trichuris Suis Ova and Autism
**note: this study is still pending**
The link between
the symptoms of autism and the body's immune system is of great interest to our
team. Specifically, we are interested in the febrile response in autism;
symptoms of autism seem to dissipate in times of fever. The effects of febrile
response in autism can be attributed to either an immune-inflammatory response
or a direct effect of temperature on clinical symptoms. In this study, we seek
to test a novel approach to ASD that will differentiate the two and would
support the immune-inflammatory mechanism of the febrile response in ASD.
In this study,
the eggs of Trichuris Suis Ova (TSO), a helmith porcine whipworm, are diluted
into a liquid and given to patients for ingestion. In turn, the ova hatch in
the small bowel and release larvae that mature into adult worms, however these
worms cannot effectively multiply in the host and are not easily transmitted to
others, hence they are not readily spread to other humans. Through an
anti-inflammatory response, TSO regulates immune function and may, in turn,
affect behavioral symptoms in individuals with autism.
Current
pharmacological approaches to autism point to immunomodulatory effects in
autism symptomatology; many FDA approved medications, prescribed for the
symptoms of autism, act on the immune system. Risperidone, an FDA approved
treatment for irritability and aggression in autism, has been found to have
immunoregulatory effects through suppression of proinflammatory cytokines.
Lithium has also been used in autism and studies of lithium have shown it also
has immunoregulatory effects.
The autoimmune
response triggered by the investigational agent may be effective in reducing
repetitive behaviors, aggression, self-injury and impulsivity. The
immunomodulatory pathways affected in ASD may not be influenced by the helminth
TSO, and there is a possibility other tests and therapies for immune function
may be a better fit for ASD. However, given its ability to inhibit the
production of proinflammatory cytokines and restore balance to the Th1/Th2
system, and its success in treating other autoimmune disorders, it stands to
reason that TSO may be a good test of the
immune
dysfunction hypothesis in ASD.
If you or your child are interested in participating in this study,
please contact Tara Kahn at (718) 653-4859 x226 or tkahn@montefiore.org
5.
Hyperthermia and Autism
**note: this study is still pending**
The link
between autism and immune function is of great interest to our team.
Specifically, we are interested in the febrile response in autism; clinical
symptoms, such as irritability, aggression and repetitive behaviors, seem to
improve during fever. This fever induced amelioration of symptoms could be due
to one of three possible causes:
1. The direct effect of temperature;
2. A resulting change in the immune inflammatory
system function associated with the infection or fever; and/or
3. An increase in the functionality of a previously
dysfunctional Locus Coeruleus-Noradrenerigic (LC-NA) system.
In this study,
we seek to directly explore the effect of increased body temperature on autism
symptomatology. Artificially increasing body temperature, we believe, may mimic
the febrile response and yield an improvement in language function, social
cognition and a decrease in disruptive behavior. The many parental reports received
regarding the improvement of symptoms during febrile episodes warrant further investigation
into the febrile hypothesis for the exploration of a possible etiology of ASD
and potential treatments that may result. The
hyperthermia hypothesis is a novel approach to simulating a febrile environment
and has not been explored in a
clinical research environment. Results from this study, whether positive or
negative, will impact knowledge of autism spectrum disorders, as they will
either provide a new avenue for treatment exploration, or rule out one of the
three potential theories regarding the febrile hypothesis.
If you or your
child are interested in participating in this study, please contact Tara Kahn
at (718) 653-4859 x226 or tkahn@montefiore.org