The Lieber Institute for Brain Development: A unique private medical research institution dedicated to research on developmental brain disorders

Changing the lives of people with schizophrenia and related developmental disorders…

www.libd.org

The burden of serious mental illness

One in four adults in America suffers from a diagnosable mental disorder. About 6 percent, or 1 in 17 —suffer from a serious mental illness. These disorders represent an enormous economic burden (in excess of $80B/year) but, more importantly, they involve great personal cost for affected individuals and their families and treatments for mental disorders are inadequate in most cases and prevention is largely nonexistent.

Genetic Association

Molecular Mechanisms of

Illness

CNS Therapies

Genetic association is an entry point into molecular mechanisms of illness

Molecular mechanisms will inform basic models for target discovery Next generation of CNS therapies requires deep understanding of molecular mechanisms of illness

Historic opportunity for discovery of molecular mechanisms of CNS disorders and novel therapeutic targets

The institutions of scientific research need to change

LIBD is heading in a different direction

Independent 501c3 not for profit medical research institution

Affiliation with the Johns Hopkins University School of Medicine

Founded by Connie & Steven Lieber and Milton & Tamar Maltz

Initial funding of $120M with $7M in State and City support

Director and CEO: Daniel R. Weinberger, M.D.

Director of Basic Sciences: Ron McKay, Ph.D.

Director of Drug Discovery: Solomon Snyder, M.D.

Chief Operating Officer: Thomas Hyde, M.D., Ph.D

Chairman of Board of Directors: Herb Pardes, M.D.

Why LIBD?: A focused mission and near-term deliverables

We are guided by our mission:

To translate basic genetic and molecular mechanisms of the developmental origins of schizophrenia and related disorders into clinical advances that change the lives of

affected individuals.

We are inspired by our founders: To transform the research landscape: providing new tools for scientific discovery

and developing new collaborative approaches to achieve our ambitious mission.

We are committed: To an interdisciplinary team effort and partnerships across academia, industry,

and philanthropy.

The path from here to there: The LIBD road map

LIBD has unique clinical and biological assets 1. Extensively phenotyped human cell lines

• Thousands of peripheral cell lines of extensively characterized patients, their healthy siblings, parents, and unrelated controls

• Unique collection of well- characterized human pluripotent ES and iPS cell

lines • > 250 fibroblast/iPS cell lines from deceased individuals whose brains also are

in LIBD

LIBD has unique clinical and biological assets 2. Human brain tissue resource 2.

LIBD: The landscape for academic and industry partnerships

The Lieber Institute’s biological materials are part of a program to

define the genetic and epigenetic regulation of human brain

development and the deviations that characterize developmental

brain disorders and also to provide historic public datasets for

collaborative research and target discovery.

LIBD: Pathways to target discovery and validation based on functional genomics

• Stem cell technologies for elucidating functional genomics and inventing

clinically relevant assays

• Functional genomics in human brain

DNA/RNA seq, epigenetics, RNA editing, mosaicism,

• In vivo physiology

• Neuro- & pharmaco-imaging genetics

• Medicinal chemistry

PGC 2 –82,000 subjects, over 100 “significant” genetic loci associated with risk for schizophrenia

How do we translate these signals into targets? From: S Ripke

Noncoding genetic variations all read out at the level of gene expression

mechanisms

RNA sequencing in brain

Functionally testing RNAs Pharmacologic use of synthetic RNAs in human stem cells

splicing miRNA

noncoding RNA enhancer/promoter effects

epigenetic state

Many genes linked to psychiatric disorders are preferentially turned on during fetal life

Nakata, Lipska et al., PNAS (2009) Nakata, Lipska et al., PNAS (2009)

Nakata, Lipska et al., PNAS (2009) Nakata, Lipska et al., PNAS (2009)

Nakata, Lipska et al., PNAS (2009)

Nakata et al., PNAS (2009)

LIBD: Understanding how genes are turned on and off in human brain

Source: Rodenhiser D, Mann M., CMAJ. 2006 174(3):341-8

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LIBD: Human Brain Epigenetic mechanisms

Colantuoni et al Nature 2011

Brain Cloud: A public database of brain development

Gene expression profiles in stem cells from William’s syndrome patients as the

cells differentiate

Developmental brain disorders can be studied in the early lives of the first cells

LIBD: resources/technology supporting the “road map”

Established expertise in transcriptomics &

human genetic analysis

Extensive iPSCs & peripheral cell

collection, leading iPS technology

In vivo models

Extensive post mortem brain

bank

Unique clinical imaging &

pharmacogenetic datasets

The LIBD road map to prioritize and validate targets Utilizing the Lieber ‘Road-Map’ to Bolster

Current and Future Projects

• Several novel targets have shown

weak signals of efficacy in traditional

Phase 2 studies in schizophrenia

• LIBD has data sets relevant to all

targets of interest.

• Request full “road-map” analysis of

targets gene, gene expression,

genetic variation, etc.

• Boost rationale for a target and

contribute to patient selection.

- e.g. mGluR2PAM, 5HT2C,

PDE10A, GlyT1

17 Author | 00 Month Year Set area descriptor | Sub level 1

Patient identification, early clinical plan

Pathway analysis and iPS assays

Risk and response genetics

Brain transcript profiling

The LIBD precompetitive CNS molecular consortium

Further exploring the complexities of the brain: UCB and The Lieber Institute For Brain Development to work together to discover new medicines

Brussels, Belgium and Baltimore, the United States, 30 June, 2013 – Both UCB and the Lieber Institute for Brain Development (LIBD) are committed to innovation and collaboration to help people living with severe brain disorders. As such, they are entering a strategic collaboration for the discovery of new drug candidates for treating patients suffering from cognitive impairment. The research alliance between LIBD and UCB reflects UCB’s “open innovation” approach that aims to generate new knowledge and capitalize on external scientific advances and expertise that complement the company’s unique internal capabilities and skills. UCB and LIBD will jointly generate novel lead compounds and further optimize them starting from chemical compounds provided by both partners. In addition, the specific interdisciplinary structure of LIBD will bring to the collaboration its unique expertise in translating basic research and drug discovery into effective clinical proof of concept.

LIBD: Scientific goals

• Establish unique and important clinical and biological material and datasets related to schizophrenia and other developmental cognitive disorders. • Characterize genetic and developmental mechanisms of schizophrenia and related developmental disorders. • Develop assays targeting implicated signaling systems and developmental processes in cell and animal models • Design algorithms based on genetics and other risk associated factors for optimizing available therapies. • Identify new potential therapeutic targets. • Test new potential treatment strategies and chemicals in basic model systems and in clinical biomarker assays.