Paul Sieving, MD, PhD

Director, NEI/NIH

RPB: Vision Research Funding Partnership II: “From Concept to Reality”

March 24, 2015.

NEI Audacious Goals Initiative - Update

NEI Audacious Goals Initiative

• Audacious Goals Initiative: a 10-15 year effort to catalyze innovation in vision research.

• Audacious Goal: to regenerate neurons and neural connections in the eye & visual system.

• Targets: photoreceptors cells and retinal ganglion cells.

• www.nei.nih.gov/audacious/

Mark S. Blumenkranz, M.D.Stanford University

John E. Dowling, Ph.D.Harvard University

Pamela A. Raymond, Ph.D.University of Michigan

Joshua Sanes, Ph.D. Harvard University

• Plots the scientific trajectory of the AGI• Identifies knowledge gaps and the expertise needed to bridge them

AGI Steering Committee

Hallmarks of AGI Funding Approach

• Stimulate projects that are innovative, catalytic, and transformative

• Encourage and develop collaborations

• Prioritize pre-clinical and translational studies, in animal and human

• Utilize cooperative agreements which allow for programmatic and scientific input and oversight by NEI

Nov. 2016 SFN (San Diego)Topic under development

NEI AGI Workshop Timeline

2016

Nov. 2014 SFN (DC)“Optic Nerve Regeneration”

2015

Oct. 2015 SFN (Chicago)“Rewiring & Reconnecting Neurons (pending)”

Feb. 2016NIH (Bethesda)“RGC Workshop”(pending)

May 2016 ARVO (Seattle)Topic pending.

May 2015ARVO (Denver)“Photoreceptor Workshop”

May 2017ARVO (Baltimore)Topic pending.

2017

When possible, workshops will be held in conjunction with SFN or ARVO annual meetings

2014

Society for Neuroscience - Nov 19, 2014 NEI AGI Workshop “Restoring Vision: Regenerating the Optic Nerve”

Chairs: Jeffrey Goldberg (UCSD) William Guido (Louisville)

Purpose:• Explore challenge and opportunity for

optic nerve regeneration

Participants: • 30+ leading researchers with expertise

ranging from developmental neurobiology to visual processing

Challenges:

• What prevents humans from regenerating retinal axons? - Other species can do it…

• Insufficient knowledge of regenerative factors - guidance cues, signaling pathways, activity-dependencies,

intrinsic and environmental changes.

• Insufficient assays for functional and behavioral tests

• Incentives for collaboration & sharing of resources and data

NEI AGI Workshop - Outcomes“Restoring Vision: Regenerating the Optic Nerve”

NEI AGI Workshop - Outcomes“Restoring Vision: Regenerating the Optic Nerve”

Ways to answer these questions:

• Comparative biology: • How do other species regenerate cells and tissues? • What factors can we harness to enable humans to do it?

-Systematically assess RGC class subsets for capacity to regenerate

• Experimental model standardization

• Imaging technology improvements

White paper release May 1, 2015 — www.nei.nih.gov/audacious

NEI AGI RFA: “Addressing Technical Needs and Opportunities for Imaging the Visual System”

• Seek projects to innovate imaging technologies

• Advance adaptive optics, image stabilization, spectroscopy, metabolic imaging, magnetic resonance imaging (MRI), and other novel technologies

• Bring new multidisciplinary teams together

• New monitoring tools are expected to yield unprecedented insight into retinal structure and function

Awards by May 2015• 4-6 funded projects, $3M-$5M total yearly costs

RFA-EY-14-001

ARVO - May 2, 2015 NEI AGI Workshop: “Photoreceptor Regeneration & Integration”

Chairs: David Gamm (Wisconsin) Rachel Wong (U. Wash)

Purpose:• Assemble experts to discuss challenges and

opportunities around photoreceptor replacement

• Review and assess methodologies—extrinsic stem cell differentiation and transplantation, intrinsic stem cell differentiation, photoreceptor transdifferentiation from Müller glia, etc.

ARVO - May 3, 2015 10:40am – 11:50am“NEI Audacious Goals Initiative Town Hall at ARVO”

Moderators: Paul Sieving (NEI) & John Dowling (Harvard)

• Moderated discussion follows the ARVO symposium, “Regenerate and Reconnect: The Road Ahead for an Audacious Goal”

• Gives symposium speakers and attendees the opportunity to discuss near- and longer-term challenges that need innovative solutions, including new technologies, methodologies and animal models.

Funding Menu

 Amount Years Commitment (per award)

Student support to attend a meeting $2K   $2K

Conference grant $50K   $50K

Career Development Award (FFB) $75K 5 $375K

K08, K23 “Clinician Scientist Development Awards”

$200K 3 to 5 $825K

K99/R00 “Pathway to Independence Award”

(mentored research / research grant)$100K & $225K 1.5 & 3 $850K

R01 Research Grant $375K 4 $1.4 million

R24 Translational Research Grant $2 million 5 $10 million

U10 Clinical Trial $1 -$4 million 5 $5 - $20 million

AGI: “Technical Needs for Imaging” RFA

4-6 awards, $1 million each

5 $25 million total for RFA

Paul A. Sieving, M.D., Ph.D.

X-Linked Retinoschisis (XLRS)

J. Haas: „ Uber das Zusammenvorkommen von Veraenderungen der Retina und Choroidea.“ Arch. Augenheilkd. 37:343 (1898).

X-linked Retinoschisis

*c

Foveal schisis GC & IPL schisis

Mid-retinal schisis

Deep-retinal space

OCT – Optical Coherence Tomography

100 uV

100 µV

XLRS Normal

a-wave - rods

b-wave bipolar

Dark-adapteddim Flash

Dark-adaptedbright Flash

Paul A. Sieving, M.D., Ph.D.

”Chorioretinal Heredodegenerations” Franceschetti, Francois & Babel (1963).

“Sex-linked Recessive Idiopathic Retinoschisis”

Paul A. Sieving, M.D., Ph.D.

Retinoschisis knockout mouse: Rs1-KO. (2004)

RS1 Targeting Vector

Wildtype Rs1 gene

Rs1-/Y Construct 1 Kb Exon 1

XbaI ClaI SmaI XbaI ClaI XbaI XbaI

Neo SmaI XbaI ClaI XbaI XbaI

XbaI ClaI SmaI XbaI ClaI XbaI XbaINeo

RSDA6 PLA2

2.4 Kb

Rs1-/Y mouseWT mouse

(#553)(#551) 50 um

Rs1 protein no Rs1 protein

WT

Rs1

-/Y

Rs1

-/-

WT

Rs1

-/Y

Rs1

-/-

2030405080

KDa

Western blot

Paul A. Sieving, M.D., Ph.D.

ERG b-wave recovery after Rs1

gene transfer indicates rescue

of synaptic transmission

Y. Zeng, et al. (2004)

Rs1 gene transfer restores function in XLRS mouse

50 ms

500 uV

AAV2-cmv-Rs1right eye

PBS left eye

- 6.4- 5.4- 4.4

- 3.4

- 2.4

- 1.4

- 0.4

0.6Sti

mul

us (l

og c

d-s/

m²)

Intravitreal injection: 13 weeks age. Analysis: 23 weeks age.

AAV2-cmv-Rs1 PBS- saline

#554 left eye#554 right eye 50 um

*

Paul A. Sieving, M.D., Ph.D.

IND Application to FDA for XLRS Gene Therapy Trial

Investigational New Drug (IND) Application

“A Phase I/IIa Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis”

Paul A. Sieving, P.I.

2250 pages plus references

Submitted to FDA: October 24, 2014

Scale of Resource

Time… time… and more time….

$7M 10 years laboratory development (2004)$1.5 M Tox study$150K GLP vector $400 K GMP vector

$1M/yr Burn rate (clinical engagement & trial support). .“EXPENSIVE”Time…

Lessons

• Research is expensive

• Research is a long term commitment

• Training and “support” are crucial to any future work

• Research is “a career”

• Sustained commitment is essential

• Private funding for “starter support” generates successes

• Principle research funding corpus is public

Bruce Alberts, Marc Kirschner, Shirley Tilghman, Harold Varmus.

“Rescuing US biomedical research from its systemic flaws.” PNAS, 2014.

• Hypercompetitive funding environment is counter-productive.• “A central flaw is the long-held assumption that the enterprise will

constantly expand.”• NIH resources are estimated 25% less than in 2003.

Gathering input• Prize competitions• AGI Development Meeting• Requests for Information (RFI)• Workshops and white papersTraining• Student travel awards • Postdoctoral fellowships • Early investigator awards• Funding for workshops or meetingsParallel funding• Funding for pilot projects, preliminary data• Targeted funding for identified knowledge gaps• Funding in areas of shared interest (photoreceptor degenerations, glaucoma)

Continued support for the entire vision research portfolio

Opportunities to Participate & Support the AGI

Critical Opportunity & Critical Need: “Training Young Investigators”

K08 Individual - laboratory based researchK23 Individual - clinical involvement T32 Institutional-based fellowshipsK99/R00 “Junior” R01 transitional awards.

Each is a 3-5 year commitment at $1 million total.

Neeraj Agarwall, PhD. NEI Training Programs Officer

NEI Audacious Goals Initiative:

AGI Update