Drug Discovery for Neurodevelopmental Disorders: Current Approaches for the Medicines of Tomorrow

BACKGROUND. Current available therapies for neurodevelopmental disorders do not address the major clinical needs in this patient population. Many of the therapeutics being progressed through the clinical pipeline are re-purposed drugs that were developed and initially thought to address broader patient populations. We take a patient-centric approach to drug discovery and start this very challenging process by understanding patient biology, and patient symptoms, to generate precision medicines that will address clinical needs of patients with neurodevelopmental disorders.

OBJECTIVES. Our goal is to generate a discovery pipeline of pre-clinical programs that will address, once they reach clinical development, major clinical needs that are present in patients with neurodevelopmental disorders. We focus on genetic syndromes where gene mutations are known to be highly penetrant and that play a very important role in disease initiation, progression and manifestation. This focus starts with a syndrome with a known genetic lesion that can then be studied at different levels (cellular, circuitry, network and animals).

METHODS. We focus on a few genetic syndromes where the gene lesion is known. We obtain patient cells that are reprogrammed to induced pluripotent stem cells and further differentiated into cellular types of interest, like neurons and neuronal subtypes as well as glia-like cells like astrocytes. These cells are characterized throughout the different stages of development in comparison with cells that do not have the genetic mutation. Differences between both genetic backgrounds are studied to understand the differences between cells from patients with gene lesions versus cells from normally developing individuals. Furthermore, we generate 3D cellular systems where a more complex relationship among cells and glia is established. These spheroids can then be used to characterize connectivity differences between neurons and glia as well as electrical recordings can be obtained to start elucidating potential changes in connectivity among these more complex cellular organizations. Finally, we generate rodent models where the same mutation (or as close as possible) that is present in our patients is present in the animal model. These models are then used to characterize potential biomarkers that resemble clinical biomarkers present in our patients, which could be used to establish relationships between drug effect and biomarker changes and ideally disease effect.

RESULTS. Initial efforts in characterizing patient-derived cells are underway in our facilities, as well as generation of spheroids from cells derived from patients. Once phenotypes are identified and characterized, we will proceed to major screening efforts of our internal compound libraries to identify chemical leads that can modify the identified phenotypes. Additionally, alternative modalities are being studied to modify/replace gene products that may be missing or in excess in patients with neurodevelopmental disorders.

CONCLUSIONS. Recent advances in genetics and genomics are enabling the understanding of the underlying biology of patients with neurodevelopmental disorders. In addition, advancement in innovative drug discovery areas like antisense oligonucleotides, gene therapy or availability of patient-derived cells to screen small molecule libraries are opening the door to future precision medicines in neurodevelopmental disorders.