quite a fascinating time to be able to
talk after the the presentation we just
heard which is the first human gene
editing trial in a rare disease and it's
really a certainly a landmark and so I'm
excited now to tell you about some of
the new things NIH is doing to really
accelerate genome editing into the
clinic and this is something that dr.
Collins mentioned briefly
how do I advance this slide how do I
advance
we can use this
okay and so this this program is that
are we talking about is funded through
the NIH Common Fund which is established
as part of the NIH roadmap and it exists
now within the office of the NIH
director and it's designed to provide a
dedicated source of funding to enable
trans-nih research and so the criteria
for programs that are funded by the
Common Fund are indicated here
they should be transformative with a high
potential to dramatically affect
biomedical and behavioral research in
the next decade catalytic synergistic
and importantly cross-cutting programs
are cut across the missions of multiple
NIH institutes and centers and to be
relevant to many diseases and
sufficiently complex to require a
coordinated trans-nih approach and
ultimately also be unique something that
no other entity is likely are able to do
and certainly accelerating genome
editing research into the clinic would
fall into that category and a lot of the
the impetus for this program is based in
part on the the advances in genome
editing that we've heard about
previously with zinc fingers but a lot
of it is also stimulated by the the
CRISPR Cas technology which is
indicated here was identified in as a
breakthrough the Year by science a
couple years ago and essentially they
kind of distinguished these two
technologies and made clear their zinc
finger approach that sandy talked about
involves proteins that bind to a
particular sequence of the DNA and make
a double strand break allowing other DNA
sequences to put in there and the CRISPR
Cas9 approach does somewhat the
same thing it also involves being a
double strand break but a key difference
is that the targeting process in the
zinc fingers actually involves the
protein so if you need to make a new
enzyme you need to make a new protein
where is it targeting within the genome
and the CRISPR Cas 9 process involves
RNA molecules that it be can be
chemically since
sighs and that's that's quite a bit more
efficient and when you think about the
sheer number of rare disease were trying
to treat and not only the number of rare
diseases but the fact that different
patients with those rare diseases are
going to have different mutations
disability this this program ability of
using RNAi to direct the enzyme to the
genome can be particularly salient and
the other I think important advance in
the in the CRISPR Cas9 field
that's come around fairly recently is
this concept of DNA base editors for a
lot of rare genetic diseases the actual
cause is a single base mutation one base
wrong out of the three billion or so in
our genome that caused the disease and
wouldn't it be great if you could
actually go into the genome and just
correct that one base and and and fix it
and do so without actually cutting the
DNA and making a double strand break and
that's what some of these base editors
and now able to do this is the work of
David Liu at Harvard and his
colleagues and essentially what they do
is they take the cast nine enzyme and
the guide RNAs to direct really a DNA
repair entity to a key to the region of
the base that you want to change that
carries a DNA repair reaction that
ultimately leads to correcting in this
case an eighty to a GC base pair and
these base editors don't correct all the
different kinds of mutations they
correct what are called transitions but
in fact transition mutations are amongst
the most common human disease-causing
mutations a single base mutations
accounting for well over half of the
human disease-causing mutations that are
known so this is a particularly exciting
technology again for these very very
rare genetic diseases and almost
personalized medicine that we're talking
about so thinking about all this the NIH
decided this is a real opportunity for
the Common Fund and we did what we often
do at the beginning of such an effort
which is get a planning group together
to get the stakeholders in and and tell
us what the needs of the community are
and we had this workshop in July of 2017
we had in scientists investigators from
both within the NIH intramural program
and many from outside we had the FDA
there we had representatives from the in
three the genome editing industry which
is obviously becoming very big and
importantly though as always we like to
do is get the voice of the patients
involved and we had Ron Bartek there
from NORD to sort of kick off the the
program and and and frame the issue and
of course Ron's here today as he always
is and some of the gaps that the groups
define the major gaps are the need for
relevant to human animal model systems
for testing cell and tissue specific
delivery systems which has come up
several times already better error free
editing machinery nucleus alternatives
assays for measuring off target effects
and long term assays and so armed to
that information those of us NIH got
together and did what we do which is
develop funding opportunities that have
now been out on the street for as we say
for about a month and I can tell you
from my own personal experience my email
inbox that they're getting no shortage
of interest from the community all
around and my colleagues are telling me
the same thing which is of course
exactly what we hope and so here are
some of the goals and and one of the
first is this is really improving the in
vivo delivering of genome editing
material obviously a very important
topic we can get to the liver but
there's many other cell types would
really like to be able to treat we just
can't get the materials there these
better animal models they will be
designed specifically for detecting
genome editing to make it easy for
people to test these systems in both
small animals and large animals because
ultimately we got to get into into human
beings looking at the unintended adverse
consequence of genome editing we talked
about off target effects and of course
we'll try to get those as low as
possible but we can identify those
effects also by DNA sequencing but the
question sometimes is isn't is an off
target effect clinically significant or
not and that gets into this real risk
benefit question that's so important for
the FDA and you really have to ask that
question in the context of the relevant
cell type because certain genes are
important in some cells and not others
so he really want biological systems
based on human cells we can evaluate
these these issues
expanding the human genome engineering
toolkit zinc fingers are obviously in
the clinic CRISPR Cas has a lot of
potential but perhaps there's something
out there that's even better that would
work better than either one and in that
case certainly that those are the things
would be interested in this is to be
clear this is not the NIH CRISPR Cas
program it's a NIH somatic genome
editing program and of course you want
to be able to coordinate disseminate all
the information that is developing this
program to be sure it gets out to the
community so people can take advantage
of it and use it and so overall what we
hope for this program is that these
these efforts will lower the barriers
for new somatic genome editing therapies
and I've emphasized somatic there
because this is an important point we
are focusing on somatic genome editing
we're not going to be supporting any
work on germline editing or editing in
cells that can be passed on to
subsequent generations and in fact one
of the goals of the animal models is to
allow us to test and be sure that the
delivery systems we use are not editing
the germline so how does this work in
terms of translation and clinical trials
so this program is not going to be
directly funding any clinical trials but
we certainly hope that it will be
accelerating those and here's sort of an
example of how we envision that working
you can imagine indeed I'm sure this is
the case that there are groups of
patient advocates thinking about doing
gene editing for their disease maybe
they've already identified that caused
of gene they can think about that it
could be edited but they're kind of
stuck because they have no way to
deliver the relevant machinery to their
relevant cell types that are so
important in their disease and so as our
investigators are developing these tools
and technologies and putting them out on
our on the website and for public
availability and these groups can come
and essentially adopt those technologies
and get them over this gap and
ultimately get into the clinic and get
an IND and not only just take the
delivery systems but in fact also
utilize some of the new tools that we're
developing for testing off target
effects and that could also go into the
ultimate evaluation of the
the risks and benefits the therapy as
part of the process and so I think the
potential impact of this this program
there's several of these increased
access to IND enabling technologies
accelerate filings of ID's for gene
editing therapies faster approval of
these editing therapies and new
therapeutic approaches for both rare and
common diseases of course today we're
focused on rare diseases but certainly
not limited to that and I often think
about how could you really sum this up
sum up the whole program in a way that
really captures the impact and as is so
often the case I think the best way to
do it is taking quote from dr. Francis
Collins you said that the focus of the
somatic cell genome editing program is
to dramatically accelerate the
translation of these technologies to the
clinic for treatment of as many genetic
diseases as possible and that's really a
sense of what it's all about and I think
is a great way to end so I'll I'll stop
there except to thank my colleagues and
the NIH working group that really spent
a lot of time doing this developing the
funding opportunities and look forward
to seeing this work
get your fruition thank you for your
attention
[Music]
we don't have a situation where it's a
single gene
