>> I'd like to thank the organizers for allowing me to participate
in the Usher Syndrome Coalition, USH Connections Conference.
It's a great pleasure to have this opportunity
to connect with the Usher Syndrome community.
Even if there is a virtual connection.
Retinitis pigmentosa is a retinal degeneration
caused by many different mutations.
Some of the mutations have
other effects in addition to retinal degeneration,
which is the case for Usher Syndrome,
in which mutations also cause hearing loss.
There are two types of photoreceptors in
the retina, rods and cones.
Mutations that cause RP cause rods
to die and have little effect on cones.
Rods are responsible for night vision and their death
makes it difficult to function in low-light environments.
But there is little problem in good lighting
doing tasks like reading or driving,
which is mediated by cones.
However, once most of the rods die from the mutation,
which often occurs in the teens,
20s, or 30s,
depending upon the mutation,
cones begin to gradually die,
resulting in slowly progressive constriction of
the peripheral vision occurring over
decades until there is tunnel vision as shown on the right.
On the left is a schematic of the retina.
The outer retina is made up solely of photoreceptors
at this layer here and 95 percent of them are rods.
After the rods die,
only cones remain and they
constitute only five percent of the cells.
Cells consume oxygen to generate energy,
and without oxygen they die.
Oxygen is delivered to
the photoreceptors from these vessels in the choroid,
which are under the retina.
The amount of oxygen that's delivered is
matched to the amount that is consumed by the cells.
After 95 percent of the cells and the outer retina die,
there's much less consumption of oxygen,
but the amount being delivered is unchanged,
resulting in a large excess of oxygen surrounding the cones.
What happens when there is an excess of oxygen?
That's illustrated in this image in the upper right,
which is an ocular section of a mouse
that was placed in high oxygen for three weeks.
The photoreceptor layer shown
here is much thinner than in a normal mouse,
where it is quite thick.
This is because most of the photoreceptors have died.
High tissue oxygen kills photoreceptors.
How does excess oxygen gradually kill cone cells in RP retina?
The excess oxygen creates reactive oxygen species,
which are highly reactive substances
that damage critical components of the cell,
lipids, proteins, and DNA.
In this schematic, the green script represents lipids,
proteins, and DNA that had been damaged.
One hit does not inactivate these molecules.
But in RP retina,
there's such a high level of reactive oxygen species,
that there's constant bombardment.
This gradually causes such severe damage to the molecules,
that they lose function.
When a critical number of these molecules become dysfunctional,
the cone cell dies.
This is a slow process that takes many months.
There's an endogenous antioxidant defense system
that can repair the damage.
But in RP retina,
the amount of reactive oxygen species
overwhelms the defense system.
One thing that can turn the tide is
exogenous antioxidants that are ingested.
They can bolster defense system and reduce
the oxidative damage that can prevent cone cell death.
N-Acetyl Cysteine or NAC is
a strong antioxidant that is
an approved drug for Tylenol overdose.
When an excessive amount of Tylenol is ingested,
it goes to the liver and breaks down into
strong reactive oxygen species
that cause severe oxidative damage to the liver,
resulting in liver failure and death.
If NAC is administered soon after the overdose,
it reduces the oxidative damage in the liver and is lifesaving.
In animal models of RP,
oral NAC reduces oxidative damage in
cones and markedly slows cone degeneration.
The promising results in animal models of RP led to
the fight RP study in which 30 patients with RP,
six of whom had Usher Syndrome,
were treated with one of
three different doses of NAC for six months.
There were small improvements in
visual function testing that
were not perceptible in everyday life.
In other words, patients didn't notice a lot of improvement.
But when their vision was tested at various ways,
there was some evidence of improvement in some patients.
More so in patients receiving
a high dose versus a low dose of NAC.
But further increases in dose above that high dose caused
upset stomach and other similar problems of the GI tract.
So the maximum tolerated dose was identified.
The small effect on cones during
six months of treatment with this dose
suggests the possibility that the cones might
be benefiting from reduction and oxidative damage.
Perhaps long-term treatment could improve
cone survival and delay the retinal degeneration.
For this reason, that
the Xiangrong Kong and I designed NAC attack,
a multicenter randomized placebo-controlled trial designed to
determine if long-term NAC slows progression of RP and is safe.
There will be 30 centers in the US,
Canada, Mexico, and Europe.
They will enroll 438 patients with RP.
This large number of patients is needed because there is
substantial difference among patients
with RP in the rate of progression.
A large study population allows us to overcome
the variability and determine if there is a treatment effect.
This is the largest study to date in patients with RP.
It is also the longest study,
about four years, because the progression of RP is quite slow.
A long treatment period will be needed to
determine if NAC reduces the progression rate.
This long duration is a burden for participating patients,
and to minimize that burden,
there will only be clinic visits every nine months with
additional visits 4.5 months after
enrollment and 4.5 months before the last visit.
>> These will be supplemented with three tele-visits and
10 phone calls to help monitor and stay connected with patients.
Nonetheless, a four-year study duration is a challenge.
To determine if RP patients were up for such a challenge.
Susie Trotochaud and her son,
Cory Dorfman, helped Dr. Kong and I design a survey.
I'd like to take this opportunity to thank any of you in
the audience who participated
in that survey because it was very helpful.
It helped us determine that the study
is feasible because the vast majority of
patients said they would be enthusiastic about
participating in a study with the features I described.
When we explain the need for
a randomized placebo-controlled study,
the survey respondents understood and were in favor of it.
Such a placebo-controlled trial is the only way to determine
with certainty if NAC provides benefit in patients with RP.
The way it works is to randomly assign patients to two groups.
In this case, 2/3 of which will be in
the NAC treatment group and 1/3 will be in the placebo group.
The random assignment ensures that
the only difference between the two groups,
despite the differences among patients within each group,
is whether they receive NAC or placebo.
Because of a large number of patients in each group,
difference between individual patients
come out in the wash and thus,
any difference in RP progression can be attributed to NAC.
Survey patients like the idea that
the study participants are twice as
likely to receive NAC as placebo.
But actually, there's little disadvantage
to being in the placebo group,
because the progression of RP is slow.
The study will be monitored by
a data and safety monitoring committee who will
perform an interim analysis after 21 months.
If there is a dramatic difference with a benefit from NAC,
patients in the placebo group will begin to receive NAC.
Our interactions with the RP community have been inspiring,
because we have found that the RP community
is like a big family concerned about each other's welfare,
and also concerned about future generations of RP patients.
They are motivated to do whatever it
takes to help find a treatment that slows
the progression of RP and thereby reduces visual disability.
We also learned from our interactions with
the RP community and individual patients with RP,
that there is a sense of urgency.
Whenever medical researchers are slow to
identify effective treatments as has been in the case for RP,
patients tend to self-medicate.
They often take vitamin supplements and herbal extracts.
In fact, there are some supplement formulations of NAC,
and I've been asked by patients if they
should consider taking such a formulation.
The answer is no,
for a number of reasons.
First, we don't know yet if NAC is helpful in patients with
RP and can't yet be sure that it is not harmful.
That is what NAC attack will determine.
Small studies are not definitive and are
not sufficient to make treatment recommendations.
An example that is particularly relevant is vitamin A.
An old, relatively small single center trial,
using a controversial outcome measure suggested
that vitamin A might be helpful in patients with RP.
A multi-center placebo controlled trial was never done.
Since there was nothing else to offer,
some physicians recommended vitamin A despite
the lack of consensus as to whether that was a good idea.
More recent studies have failed to show
any benefit from vitamin A, and in fact,
have shown that patients with a mutation in
a particular gene called ABCA4,
which can cause RP and more commonly causes Stargardt disease,
are harmed because vitamin A speed's their degeneration.
A second reason to avoid
supplements is that unlike prescription drugs,
they are unregulated so that
manufacturers don't have to document what is in them.
When NAC supplements have been analyzed,
they often have less NAC than stated on the label,
and have contaminants, some of which can be harmful.
There are well-documented examples
of supplements that have caused harm.
Supplements are multi vitamins that contain Beta-carotene,
increase the risk of lung cancer in smokers.
Omega-3 fatty acids increase the risk of depression.
Some herbal extracts cause kidney toxicity.
This slide shows references that support
the concerns I've mentioned regarding supplements and vitamins,
and call into question whether any of us should be taking them.
The US Preventive Services Task Force analyzed
84 studies and found
little evidence that vitamins and minerals prevent cancer,
cardiovascular disease, or increased lifespan,
and confirmed that Beta-carotene is harmful to smokers.
Despite overwhelming evidence that
supplements and vitamins provide
little or no benefit except in
pregnant women and can be harmful in some individuals,
US adults spend more than 10 billion dollars
a year on vitamins and supplements.
A major factor is that misleading marketing by manufacturers
making large profits falsely contradicts scientific studies.
Consumers who are conditioned to think of
vitamins and supplements as natural and good,
prefer to believe the misinformation.
In conclusion, oxidative damage
contributes to cone dysfunction and degeneration in RP.
NAC is a strong antioxidant that reduces oxidative damage.
NAC attack is a randomized placebo-controlled multicenter trial
that will test whether NAC can slow progression of RP.
The results are of critical importance to the RP community,
because if they are favorable,
it will mean lifelong treatment with NAC in all patients with RP,
which is a big commitment.
The current lack of an effective treatment for RP
is frustrating for patients and physicians.
Although human nature prefers action to inaction,
it is best to avoid self-medication with
supplements and wait for
definitive recommendations from clinical trials.
If you have any questions or would like more information,
please contact us at NACAttack@jh.edu.
I once again, thank the organizers for
the privilege of presenting this information to you. Thank you.