Update: Midbrain/Hindbrain Malformations & Hydrocephalus

NINDS is committed to funding research to better understand hydrocephalus and to develop new and improved diagnostic methods and treatments.   In June 2014, NINDS convened the two-day workshop “Midbrain/Hindbrain Malformation and Hydrocephalus: Understanding the Causes, Consequences, and Gaps in Understanding” in cooperation with the Hydrocephalus Association, Chiari & Syringomyelia Foundation, and the Dandy Walker Alliance.   The workshop considered the implications of recent advances in neuroimaging which have led to the in utero identification of developmental malformations of the brain including those leading to hydrocephalus as well as the remarkable progress in the identification of disease genes.  All of these advances have the potential to lead to early detection, enhanced diagnosis and new therapeutics.  However, currently, there is an inconsistency in the detection, diagnosis and classification of these disorders; these result in numerous clinical issues for the patient populations including unnecessarily terminated normal pregnancies in the worst cases, as well as resultant multiple confusing and conflicting diagnoses leading to inconsistencies in counseling and treatment for others.  In addition, despite the numerous gene identifications, a clear biological pathway involved in the pathogenesis of these disorders has yet to be defined.  

To address these issues, over 35 scientists, clinicians and advocacy members came together to address the four main objectives of the workshop.  The first objective was to address classification and diagnosis of disease; is the pre-natal malformation predictive of patient outcome and do the structural features correlate with the natural history.  The second objective was to examine the genetics of midbrain/hindbrain malformations and hydrocephalus and to ask the question is there a common biology. The third objective was to examine the current animal models of midbrain/hindbrain malformations and hydrocephalus and to discuss what we can learn from the current models and to determine if new models are needed.  Finally, the fourth objective was to examine new models for thinking about midbrain/hindbrain malformations and hydrocephalus and potential treatments.  The objectives were designed to facilitate both the basic and clinical research in midbrain/hindbrain malformations and hydrocephalus with the long term goal to enhance the detection, diagnosis and classification of these disorders as well as to identify potential biological pathways to lead to new therapeutics. 

Among the major recommendations of the workshop were the need for an understanding and classification of the disease based on mechanism rather than on just clinical or radiologic findings, centralized biobanking and data repositories, natural history studies of hydrocephalus, and better animal models for study of disease mechanisms and treatment in the laboratory.  Since the meeting convened, there have been multiple funding opportunities that become available that will allow investigators to address these gaps in knowledge.  First, NINDS has a new funding opportunity (PAR-16-020) that invites researchers to submit applications for support of clinical projects that address critical needs for clinical trial readiness in rare neurological or neuromuscular diseases/conditions. Components of trial readiness may include knowledge of the course of disease necessary for selecting cohorts of patients with defined characteristics, and validation of clinical outcome measures or biomarkers appropriate for assessing response to the intervention. By supporting studies aimed at clinical trial readiness, the NINDS intends to accelerate the testing of candidate therapeutics and increase the likelihood of successful trials.  In addition, NINDS has developed a series of funding mechanisms to facilitate translational research.  One of these mechanisms (RFA-NS-16-013) encourages the development and validation of: 1) animal models and human tissue ex vivo systems that recapitulate the phenotypic and physiologic characteristics of a defined neurological disorder and/or 2) clinically feasible pharmacodynamic markers for therapeutics designed to treat neurological disease.  In addition, NINDS also supports a funding opportunity related to innovative therapies and tools for screenable disorders in newborns (PAR-14-270). Through this funding opportunity, NINDS supports activities needed as a prelude to, or that are supportive of, clinical trials (e.g., outcome measure development, genotype-phenotype relationships, natural history studies, etc.) in order to facilitate development of therapies in screenable neurological disorders. 

Finally, NINDS is planning a follow up meeting for 2017 on perinatal/pediatric hydrocephalus focused on understanding the etiology, development of scientific resources, including animal models and cell lines, and potential therapeutics.  Together these two workshops will inform NINDS and the scientific community on the state of the science and on priorities for moving forward.