Shenandoah Robinson, MD, PhD, Johns Hopkins University
Making the Most of Mother Nature: Neonatal Combinatorial Therapy with Endogenous Neurorepair Agents
Preterm infants are prone to cerebral palsy and associated learning and behavioral problems caused by early brain injury, reduced placental blood flow and intrauterine inflammation.
This study proposes the use of a novel combination of Erythropoietin (EPO) and Melatonin (MLT) to repair the developing brain and spinal cord following early, neonatal brain injury. Both EPO and Melatonin therapies have been proven safe in children and we predict that administering the two together for newborns who have suffered brain injury will support early repair of the brain and reduce the likelihood of a CP diagnosis and other developmental concerns.
Dr. Zachary Vesoulis, Washington University
Newly Developed Oxygen Monitoring Systems to Reduce CP-Related Brain Injury
Premature babies experience frequent and often severe fluctuations in oxygen levels, making them ten times more likely to suffer Injury that causes cerebral palsy. Although this occurrence is well known, the current standard of care for affected newborns does not involve routine monitoring of oxygen levels in the brain, making it difficult to adjust oxygen treatment with the aim of reducing brain injury. In this study, we will test a novel method for monitoring brain oxygen levels that will provide personalized guidance for oxygen management and reduce CP-related brain injury.
Dr. Zachary Vesoulis, Washington University
NIRS Monitoring to Stop Injury
The current standard of care monitoring (pulse oximetry) for premature infants provides inadequate information to guide ventilator and oxygen management for optimal neuroprotection. Near-infrared spectroscopy (NIRS) is a light-based non-invasive device, approved for use in neonates, which provides information about oxygen levels in the brain, something not
easily available in any other way.
There are an increasing number of reports which link low oxygen levels to brain injury and it is a high-priority target for intervention.
This project will randomize preterm infants to either a “standard of care” group or a “NIRS-directed”group. In this second group, the infants will have NIRS monitoring for the first 72 hours after birth. If their brain oxygen level goes outside of the normal range, a standardized treatment protocol using evidence-based strategies will be employed. The primary outcome of this study will be a reduction in death or severe brain injury.
This project was piloted in a group of 166 infants with a remarkable 25% reduction in this outcome, suggesting significant potential benefits.
Dr. Srinivas Manideep Chavali, University of California, San Francisco
Improving Myelin Production as a Therapeutic Strategy to Treat CP
Babies who suffer an oxygen deprivation event at birth are at high risk of developing cerebral palsy. This study looks closely at oligodendrocytes, a special brain cell that is responsible for the generation of myelin, a vital brain component that ensures proper nerve signal transmission and brain development. In this study, we’ll look closely at signaling targets that inhibit myelin production, and test a hypothesis of blocking the signals as a therapeutic strategy to treat CP.
Nathalie Maitre, MD, Nationwide Children’s Hospital, Columbus, OH
RCT of Feeding Intervention with Pacifier Activated Device and Mother’s Voice in Infants at High-Risk for Cerebral Palsy
Our proposal addresses the frequent feeding difficulties of infants at high-risk for CP. We aim to improve their oral feeding skills very early on in life, while still in the NICU, to decrease long-term feeding-related problems.
We will employ a training intervention using a pacifier-activated device with mother’s voice as positive reinforcement for stronger and more rhythmic sucking, compared to sucking separately from mother’s voice. Following the Guidelines for Early Detection of CP, we will include NICU infants with specific brain injury or with abnormal General Movements Assessments and follow their outcomes in the first year.
Dr. Evelyn Shih, Children’s Hospital of Philadelphia
Dissection of the Bioenergetic Network of the Neurovascular Unit in Focal Ischemic Stroke: Building a Foundation to Design Mitochondrial Therapeutics for Childhood Stroke
Stroke is the most common cause of hemiparetic cerebral palsy. Ischemic stroke occurs when a blood vessel to the brain is blocked, resulting in brain cell death. Stroke affects ~5,000 children in the USA yearly. The risk of stroke is highest around the time of birth (perinatal), occurring in ~1 in 4000 live births. Up to 70-80% of children who suffer perinatal stroke develop cerebral palsy.
Currently, the only treatment for stroke is restoring blood flow through the blocked vessel. Unfortunately, >90% of children and all babies with stroke are not eligible for these treatments. Thus, new treatments are needed.
Mitochondria are the “energy powerhouse” of the body. In stroke, mitochondria become dysfunctional and cause harm, leading to brain cell death. We aim to identify mitochondrial targets for new treatments. In order to design effective treatments, we first need to understand the changes that occur within mitochondria during stroke and how these cause cell death. This study uses a novel mouse model of childhood stroke to investigate the effect of mitochondrial dysfunction in two main brain cell types (neurons and astrocytes).
Using genetic engineering, we will induce mitochondrial mutations in neurons and astrocytes, separately, and measure stroke size and motor disability. We postulate that selective mitochondrial dysfunction in neurons will be protective by reduction of damaging oxidative stress. In contrast, we hypothesize that selective mitochondrial dysfunction in astrocytes will be harmful due to the loss of cues that keep brain cells alive. Thus, a treatment that indiscriminately affects mitochondria in all cell types would be unlikely to work. We will test a potential cell-selective therapeutic strategy to
reduce stroke severity. This study has high potential to illuminate new approaches for treatments to reduce brain injury and improve stroke-related disability, including cerebral palsy.
Assistant Professor Colleen Peyton, DPT, Northwestern University
The Ontogeny of Fidgety Movements in Infants At Risk of Cerebral Palsy
This study is an international collaboration between the United States, Australia, and Italy.
The international guidelines for the early detection of cerebral palsy (CP) established a decision-making framework to facilitate earlier and more accurate diagnosis of CP in infancy. The Prechtl General Movement Assessment (GMA) is a clinical tool that was recommended as one of the best motor assessments to identify CP in infants less than five months old. While the GMA has been proven to be a robust predictor of CP, the age at which the test is most accurate is less clear.
The presence of “fidgety movements,” an age-specific marker of typical motor development, was traditionally believed to be present and detectable at 12 weeks post-term age. However, in the years since the guidelines have been published, new evidence has emerged challenging this time frame. The emergence of fidgety movements should be studied rigorously as there may be variation among high-risk groups. This has not yet been tested in a large, diverse sample of infants.
Our objective is to understand the time at which the GMA is most effective to improve accuracy of early detection of cerebral palsy. We will compare the onset of fidgety movements in children with medically complex histories to a healthy control group. Parents will be able to obtain GMA data at six time points in development (10, 12, 14, 16, 18, 20 weeks post-term age), using the Baby Moves smartphone application.
Over the course of two years, infants from Europe, Australia, and North America will be enrolled in the study. The movements will be analyzed by expert GMA assessors to determine the time when fidgety movements are most clearly present.
It is imperative that clinicians following the early detection guidelines understand the optimal time to use the GMA in order to accurately identify infants with CP.
Dr. Alexander Hoon, Kennedy Krieger/Johns Hopkins
Over 80% of the 17 million children and adults living with cerebral palsy suffer from daily debilitating pain, which greatly diminishes quality of life. We know with greater understanding of the cause(s), pain symptoms are both preventable and treatable. Our intensive 2018 chronic pain study will look closely at the impact of individual injuries that lead to CP and discern how pain symptoms correlate with sensation and specific abnormal biomarkers. Through this study, we will identify people with CP who are most at risk for suffering chronic pain, so pain symptoms can be prevented and treated effectively through early interventions.
SpineX
Fine-Tuning the Nervous System With Neuromodulation
SpineX Inc. is an early stage bioelectric medtech company developing noninvasive neuromodulation devices. SpineX is committed to helping individuals with unmet clinical needs. Our goal is to use rigorously tested neuromodulation technologies to aid recovery and restoration of several functions for people with cerebral palsy, including bladder, bowel, and sensorimotor function.
CPARF’s current grant supports ongoing clinical and device development for Spinal Cord Innovation in Pediatrics (SCIP) to enable voluntary movement and control for children with cerebral palsy. SCIP is recognized by the FDA as a breakthrough device.
Dr. Dawn Gano, University of California San Francisco
Trexo Robotic Exoskeleton Training in Non-Ambulatory Children <2 Years (TREx) Study
New strategies to improve motor function in young children with cerebral palsy (CP) are needed. Our goal is to bring children with CP to the forefront of the implementation of robotic exoskeleton technology. We will conduct the first study of robotic exoskeleton training in children with delayed motor skills or a diagnosis of CP at ages 1-2 years.
We will recruit 10 children to participate in an exoskeleton-training program to determine the acceptability and feasibility of robotic rehabilitation. We will evaluate whether the exoskeleton improves range of motion, strength and/or motor function. To learn how robotics may address the needs and rehabilitation goals of participating children, we will conduct interviews and focus groups with parents of participants and clinicians.
The long-term goal of this study is to apply what we learn to the design of a clinical trial that can
determine if exoskeleton rehabilitation is more effective than standard rehabilitation.
Dr. Leigh Hochberg, Principal Investigator, and BrainGate researchers at Massachusetts General Hospital, Harvard, Brown, Case Western Reserve, and Stanford Universities
Thought-to-Speech: A Life-Changing Brain-Computer Interface System for Communication
Effective communication is fundamental to independence and participation in social, educational, and employment opportunities. Yet, a quarter of people living with cerebral palsy cannot talk and even more have co-occurring mobility challenges that inhibit their ability to use current assistive communication devices. Even the most advanced adaptive communication systems, such as eye gaze, remain extremely cumbersome, fatiguing and slow for many consumers, setting them back in our rapid response society.
Technology and modern computer science are driving change at a rapid pace, and if effectively leveraged, speech may be unlocked for millions of people who were once considered permanently nonverbal. Harnessing this transformative time, CPARF, along with world renowned research team, BrainGate, has launched a world-first initiative to develop a revolutionary communication system, called “Thought to Speech (TTS)”, a technology that leverages recent advances in computer science and brain-computer interface (BCI) to generate real-time speech, bypassing many of the impediments of currently available augmentative devices. The current goal is to launch clinical trials of a Thought-to-speech device for CP in 2021.
Evan Snyder, MD, Sanford Burnham Prebys Medical Discovery Institute
Evaluating the Synergistic vs. Antagonistic Actions of Human Neural Stem Cells in combination with Hypothermia for Neuroprotection in Perinatal Hypoxic-Ischemic Brain Injury
Lack of blood flow & oxygen to the newborn brain (called “hypoxic-ischemic injury [HII]”) remains a devastating & common problem with serious lifelong neurological consequences, including CP, severe motor, sensory and cognitive impairment, epilepsy, learning disabilities, & autistic behaviors.
The cost to the US economy is more than one million dollars per child for life-long medical and rehabilitative care; the indirect costs based on the impact on family dynamics is 2-5 times more. Presently there is no treatment or even an accurate predictor of this type of injury. The current, most modern clinical intervention is immediate head and body “cooling”, which only helps modestly and only if started within the few hours of life, meaning that many babies miss the tight window for this sub-optimal therapy.
We have strong evidence that neural stem cells may repair and protect at risk regions of the brain subjected to HII. We have also devised a brain imaging strategy for monitoring the evolution of the injury, selection of appropriate patients and tracking improvement. Any new interventions for HII must be coordinated with cooling which is now standard-of-care. Yet, it is not known how to coordinate the administration of these two modalities in a way that enables them to work complementary with each other and not antagonistically. Once we have answered this question, we are prepared to request permission from the FDA to launch a clinical trial in babies at high risk for CP. There is a dire need for better, later and more broadly-applicable treatments against HII that better target injuries. If we can identify a treatment that reduces the morbidity associated with neonatal HII, the benefits for affected infants and children, their families and society at large would be enormous. In addition, brain imaging paradigms to be used in this proposal could be applied to many acquired or degenerative neural diseases of all ages.
Dr. Joanne Kurtzberg, MD, Duke University
Mesenchymal Stem Cells (Derived from Extracellular Vesicles) for Repair after Neonatal StrokeA Phase II, Multi-Site Study of Autologous Cord Blood Stem Cells for Hypoxic Ischemic Encephalopathy
Cerebral palsy results from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult or hemorrhage. Currently available treatments for patients with cerebral palsy are supportive, but not curative. Umbilical cord blood (UCB) has been shown to lessen the clinical and radiographic impact of hypoxic brain injury and stroke in animal models. UCB also engrafts and differentiates in brain, facilitating neural cell repair, in animal models and human patients with inborn errors of metabolism undergoing allogeneic, unrelated donor UCB transplantation. We hypothesize that, in the setting of brain injury, infusion of autologous UCB will facilitate neural cell repair resulting in improved function in pediatric patients with cerebral palsy.
In this Phase II study, multi-site study we will test the safety and efficacy of the infusion of a baby’s own (autologous) umbilical cord blood as compared with placebo in babies born with history and signs of hypoxic-ischemic brain injury.
Dr. Peter Sheng Chih Jin, Washington University in St. Louis
Discovery of Novel Genetic Variations in Cerebral Palsy by Whole Genome Sequencing
Cerebral palsy (CP) is a major neurodevelopment disorder and the most common lifelong physical disability. Although CP is commonly associated with prematurity or prenatal brain injury, accumulating evidence suggests that deleterious genetic variants may contribute to CP, in addition to environmental insults. However, the genetic causes of most CP cases remain unclear. Further, attempts to measure the effects of genetic variations have been limited.
We will analyze genetic information from CP families to identify genetic risk factors and perform functional studies to provide mechanistic insight into identified genetic variations. This work can identify novel genetic causes for therapeutic intervention and increase precision in genetic counseling, outcome prognostication, and treatment stratification, while informing future clinical trial design.
Dr. Michael Kruer, Board of Regents, University of Arizona
Predicting Response to Deep Brain Stimulation Through Genomic Classification of Dystonic Cerebral Palsy
Dystonia affects one in six people with cerebral palsy, making it very difficult and sometimes impossible to control movement. Deep brain stimulation, a cutting-edge form of neuromodulation in which electrodes are strategically placed in the brain, is proven to be a dramatically effective treatment in many people with dystonic cerebral palsy. However, there are some cases in which individuals do not respond at all to the treatment, making outcomes extremely difficult to predict and presenting challenges to both families and physicians when deciding to prescribe and proceed with the invasive procedure. This study will test a novel approach that combines genomic findings with detailed clinical data to predict which individuals are top candidates for Deep Brain Stimulation and most likely to see significant improvements.
Dr. Sara Lewis, Phoenix Children’s Hospital
Delivering Personal Medicine and Identifying Dystonic CP Genes and Pathways
Instead of one disorder, researchers are finding that cerebral palsy (CP) includes a mix of genetic disorders. This creates both a need and opportunity for personalized medicine in CP. However, many of these genes are unknown, uncharacterized, or lack treatments. Where treatments are known, patients who would benefit are missed because of lack of access to genetic testing.
A feature of CP that needs better treatment options is dystonia. Dystonia is abnormal muscle contractions causing unwanted movements or postures that can cause pain and profound impairments in daily tasks. The genes and cell changes that cause dystonia are mostly unknown, which has made it very difficult to develop treatments.
This project focuses on creating a list of genes found in dystonic CP patients and adults with dystonia.
Some genetic causes of CP have known treatments that would improve patient outcomes. These can be missed since many clinicians and healthcare decisionmakers don’t know how genetic testing could benefit patients with CP.
Clinicians, scientists, and geneticists on this project will bridge this gap by creating a report of genes found in patients from clinical testing and research studies. This project also entails the search for treatments known to be effective for these genetic causes in peer-reviewed clinical studies.