NIH Blueprint empowers drug development for nervous system disorders
The National Institutes of Health has made awards to investigators across
the United States for an ambitious set of projects seeking to develop
new drugs for disorders of the nervous system.
The projects — aimed at treating conditions such as vision loss,
neurodegenerative disease and depression — are funded through the
NIH Blueprint for Neuroscience Research. The NIH Blueprint pulls
together 15 of the agency’s institutes and centers, leveraging their
resources to confront major, cross-cutting challenges in neuroscience
research. The Blueprint
Neurotherapeutics Network will serve as a resource enabling investigators
to develop new drugs for nervous system disorders and prepare them for
clinical trials, and will be funded at up to $50 million over five years.
For decades, public funding from NIH has helped academic labs and small
businesses use their ingenuity to pursue new strategies for treating
nervous system disorders. However, many labs often lack the resources — time,
money, scientific staff, and regulatory expertise — to turn a promising
strategy into an effective treatment. The new initiative places
these investigators at the helm of an expert drug development team that
includes pharmaceutical industry consultants and service contractors.
“The Blueprint Neurotherapeutics Network will pair neuroscientists
with experts in therapy development, and enable them to pursue their
most exciting ideas for new drugs without having to redirect the focus
of their laboratories,” said Story Landis, Ph.D., director of NIH’s
National Institute of Neurological Disorders and Stroke (NINDS), which
is a member of the NIH Blueprint.
Nervous system disorders affect tens of millions of Americans, and there
is a substantial unmet need for treatment. But the process for
developing new drug therapies is costly and carries high risk. Only
about 10-20 percent of candidate drugs for all disease indications survive
the early phases of development and reach clinical trials. And
development of treatments for disorders affecting the nervous system
may face special hurdles. For example, many such disorders are
individually rare, which means they present small markets for drug companies.
Before a new compound can move into clinical trials, its chemical structure
must typically be redesigned to transform it into a safe and effective
drug, a process called chemical optimization. Hundreds of chemical
variations must be tested and retested in cell-based systems and animal
models to find one with the desired effects.
Project teams supported by the Blueprint Neurotherapeutics Network receive
research funding, plus access to millions of dollars worth of services
normally only available to pharmaceutical companies. The pharmaceutical
and biotechnology industry consultants will assist investigators throughout
the drug development process, from chemical optimization, to biological
testing, to advancing the drug into early-stage clinical trials. Each
project team will be required to meet a set of interim goals, or milestones,
to continue to receive funds and access to Blueprint resources.
The Blueprint has made awards to seven research teams at six academic
institutions and one drug discovery company. Detailed information
about the seven projects is available at http://neuroscienceblueprint.nih.gov/bpdrugs/bpn_participants.htm. The
project teams and their strategies are:
- Brigham and Women’s Hospital, Cambridge, Mass., and Ohio State University,
Principal Investigators: Marcie Glicksman, Ph.D., Gregory Cuny,
Ph.D. and Chien-Liang Lin, Ph.D.
Disorder: Amyotrophic lateral sclerosis (ALS)
Strategy: To slow the onset of paralysis in ALS by reducing toxic
levels of the brain chemical glutamate. The compounds under study
work by stimulating EAAT2, a protein that enables cells to essentially
vacuum up excess glutamate.
- Columbia University, New York City
Principal Investigator: Konstantin Petrukhin, Ph.D.
Disorder: Age-related macular degeneration (AMD)
Strategy: To slow the course of dry AMD, which occurs when cells
in the eye degenerate, due in part to the chemistry of vision. A
derivative of retinol (a form of Vitamin A) is needed for vision, but
it also generates a toxic byproduct. The compounds under study
would reduce retinol levels in the eye.
- Emory University, Atlanta
Principal Investigator: Raymond Dingledine, Ph.D.
Strategy: To pharmacologically enhance the activity of EP2, a receptor
for prostaglandins. Prostaglandins are primarily known for their role
in inflammation, but activation of the EP2 receptor has protective
effects in animal models of stroke.
- Trevena, Inc., King of Prussia, Pa.
Principal Investigator: Michael William Lark, Ph.D.
Strategy: To develop faster antidepressants that tap into the
body’s system of natural feel-good chemicals known as endorphins. The
compounds under study activate the delta-opioid receptor, which is
involved in the brain’s response to endorphins.
- University of California, San Diego
Principal Investigator: Steven Wagner, Ph.D.
Disorder: Alzheimer’s disease
Strategy: To develop selective modulators of an enzyme responsible
for producing Abeta-42, a protein fragment that accumulates in the
brains of people with Alzheimer’s disease. Abeta-42 is
believed to play a critical role in brain cell death and dementia.
- University of Miami, and Miami Project to Cure Paralysis
Principal Investigators: John Bixby, Ph.D., Vance Lemmon, Ph.D.
and Jeffrey Goldberg, M.D., Ph.D.
Disorder: Optic neuropathy (damage to the optic nerves)
Strategy: To develop compounds that help injured fibers in the
optic nerve regenerate and grow through scar tissue. Damage to
the optic nerves, which connect the eyes to the brain, is a common
cause of vision loss.
- University of Washington, and Fred Hutchinson Cancer Research Center,
Principal Investigators: Edwin Rubel, Ph.D., David Raible, Ph.D.
and Julian Simon, Ph.D.
Disorders: Hearing loss and balance disorders
Strategy: To develop compounds that prevent the damaging effects
certain antibiotics and anticancer drugs can have on cells inside the
ear. The team is testing compounds in larval zebrafish, which
use similar cells to detect vibrations in water.
“The investigators get access to the same resources and expertise
that drug companies have,” said Jill Heemskerk, Ph.D., a program
director in the NINDS Office of Translational Research and the lead contact
for the Blueprint Neurotherapeutics Network. “The investigators
will retain intellectual property rights for any drugs they develop through
the network. Our hope is that pharmaceutical companies will license
the most promising drugs and invest in the clinical studies needed to
bring them to market.”
The Blueprint Neurotherapeutics Network has issued another request
with a deadline of Dec. 15, 2011. Given that only 10-20 percent
of the compounds under investigation are likely to survive preclinical
development, the network will fund as many as 20 projects, with the
goal of bringing at least two to four compounds into early clinical
trials. Applicants must have at least one lead compound, as well
as the biological assays for evaluating derivative compounds made during
the optimization process.
The NIH Blueprint for Neuroscience Research (www.neuroscienceblueprint.nih.gov)
is a cooperative effort among the NIH Office of the Director and the
15 NIH Institutes and Centers that support research on the nervous system.
By pooling resources and expertise, the Blueprint supports transformative
neuroscience research, and the development of new tools, training opportunities,
and other resources to assist neuroscientists. The Blueprint Neurotherapeutics
Network is one of the Blueprint Grand Challenges, which are intended
to promote major leaps in the understanding of brain function and in
approaches for treating brain disorders. For more information,
NINDS (www.ninds.nih.gov) is the
nation’s leading funder of research on the brain and nervous system. The
NINDS mission is to reduce the burden of neurological disease — a
burden borne by every age group, by every segment of society, by people
all over the world.