NEW characterizing rate of progression in USHer syndrome (NEW-USH) study
a natural history study in patients with Usher syndrome

Mutations in USH2A give rise to two phenotypes: Usher syndrome type IIa (USH2A)
and nonsyndromic RP (USH2A associated nsRP). Usher syndrome is the most common
form of congenital deafblindness. Patients with Usher syndrome are hearing
impaired or profoundly deaf from birth and can be rehabilitated with hearing
aids or a cochlear implant. Patients with USH2A associated nsRP do not suffer
from early onset hearing loss. However a study by Hartel et al. showed us that
in half of the studied patients a (subclinical) mild hearing impairment is
present[1]. The study by Iannaccone et al. showed us similar results. Both
USH2A and USH2A associated nsRP are most importantly characterized by the
development of retinitis pigmentosa (RP), a slowly progressive type of retinal
degeneration that usually starts in the first to third decade of life. This
leads, in the majority of patients, to become visually impaired between the
ages of 40-50. There are no treatment options for the retinal degeneration. The
hearing impairment is treated with hearing aids and later cochlear implantation.
Usher syndrome leads to reduced mobility and social isolation. In addition,
studies in the United States indicate that healthcare costs for patients with
Usher syndrome are $7,000 higher per person than for the average population. In
the Netherlands, there are an estimated 600-850 individuals with this syndrome.
Usher syndrome is an autosomal recessively inherited disorder and is known to
be genetically heterogeneous. Currently, 10 Usher syndrome genes have been
identified. Research nowadays is, however, shifting from gene identification
and functional analysis of encoded Usher syndrome proteins towards development
of (genetic) therapies to treat Usher syndrome-related blindness and hearing
loss. As the retinal symptoms manifest during the first to third decade of
life, there is a window of opportunity to stop the progression before onset of
symptoms or in an early stage of the disease.

Radboudumc and Usher syndrome
The Dutch Ministry of Health has awarded the Radboud university medical center
as center of expertise for Usher syndrome. Usher syndrome has been one of the
main research topics of the departments of Otolaryngology and Ophthalmology at
the Radboud university medical center in Nijmegen for more than 3 decades. Over
these decades, numerous phenotype studies on the auditory and visual phenotype
in Usher syndrome have been performed in our center. Based on the interaction
with patients in clinic and the creation of multiple national platforms
(ushersyndroom.nl, SWODB and the contact group for Usher patients of the
Oogvereniging) for Usher syndrome that create awareness for the disease, we are
now in contact with more than half of the estimated patients with Usher
syndrome in the Netherlands. Over the past decades, genetic research on Usher
syndrome in our center mainly focused on the identification of genes, related
functions of encoded proteins and more recently the development of gene
therapy. Many papers on these subjects have been published. Recently, in
addition to the first three subtypes of the disease, a fourth subtype of Usher
syndrome has been identified by the genetic research group at the Radboudumc.
Furthermore, has the connection between sleep quality and Usher syndrome been
made by this research team.
More recently, research in Ophthalmology is shifting towards detailed natural
history studies using advanced and state-of-the art imaging modalities because
of its importance to allow identification of treatment effect in genetic
therapy studies.

Natural history studies of visual function in Usher syndrome are the basis for
evaluating future genetic therapy
To measure the interventional effect of a (genetic) therapy, it is crucial to
know the detailed natural course of the visual deterioration over time. Several
genetic therapy studies for other retinal disorders are currently delayed
because the natural history has not been studied in depth. It is therefore
essential to start natural history studies as early as possible.
Our previous phenotype studies of the past decades were retrospectively
performed and are not suitable and extensive enough to reconstruct a thorough
view on the natural course of visual deterioration in Usher syndrome. To
address that problem, in 2018 the Characterizing Rate of progression in USHer
syndrome (CRUSH) study was initiated at the Radboudumc.

Over a period of four years, we collected a substantial amount of data from
patients with Usher syndrome type 2. Although this study was concluded in
October 2024, we aim to gather additional data to gain deeper insights into the
progression of the disease. We want to continue the follow-up of these patients
to gain a better insight in disease progression and use additional
state-of-the-art imaging techniques that allow for more detailed structure and
function correlations. Therefore, not all tests from the original CRUSH study
will be repeated; we will focus solely on those that demonstrated disease
progression and show potential as endpoints in future clinical trials and we
will add the newest, non-invasive state-of-the-art imaging techniques. Taken
into account that the international Rate of Progression in USH2A-Related
Retinal Degeneration (RUSH2A) study indicated the same tests showing potential
as future clinical trial endpoints, it is of major importance to gain further
data on these measurements[36]. Further information is needed on these tests
to determine whether they can effectively track disease progression for
upcoming clinical studies. By conducting this study, we aim to demonstrate
either the validation or refutation of the potentially useful measurements.
Throughout the CRUSH study, new imaging technologies like Adaptive Optics(AO)
have been developed that allow for more detailed information on
structure-function correlations than for example the regular OCT images. These
structure and function correlations are of major importance and provide
comprehensive information on the retinal site of interest; namely, they allow
for the identification of the exact location where retinal cells are on the
verge of apoptosis. In other words, the position where treatment effect can
likely be best observed. We want to add this Adaptive Optics as a test in our
study, to determine whether this test can be used as a future clinical endpoint
in a genetic therapy trial, as was stated in several studies.

The study will help us to determine 1. the necessary type of (combined)
examinations and 2. the sample size that is essential to evaluate (future)
genetic therapy in Usher syndrome type 2 and USH2A associated nsRP.

Longitudinal, prospective natural history study of Usher syndrome or USH2A
associated nsRP patients with a one-year follow up for a total of two years.
This observational study will provide reliable data on the natural history of
Usher syndrome and USH2A associated nsRP.

Participants do not benefit, risks are considered negligible and procedures are
non-invasive.

Most of the study procedures are considered part of standard care. There are no
known risks beyond those involved in standard clinical care. The risks and
discomforts that may be involved in the usual care of the patients during the
period of time of prospective data collection:

- Visual acuity testing, (micro)perimetry and questionnaires require time and
concentration of the patient, which might cause frustration, but no lasting
adverse effects are associated with these non-invasive tests.
- Dilating eye drops will be used prior to fundus photography, OCT, FAF, FST,
and microperimetry. Dilating eye drops cause a blurry vision for a few hours,
and may sting, cause light-sensitivity, or an allergic reaction. There is a
very small risk of inducing a narrow-angle glaucoma attack from the pupil
dilation. Since all participants will have had prior pupil dilation usually on
multiple occasions, the odds of the event in these patients are even smaller.
If glaucoma occurs, treatment is available. Participants are instructed to
contact our department in the extremely unlikely event of eye drop-induced
glaucoma.
- IOP measurement: In rare instances, the cornea may be scratched during
measurement of intra-ocular pressure. An abrasion like this may be painful, but
it heals quickly with no lasting effects. In the event that a participant
experiences a corneal abrasion, an eye patch may be placed over the eye.