Project Summary
Sialidosis is a rare, fatal, neurological disorder caused by a mutation in the NEU1 gene resulting in vision loss,
seizures, involuntary myoclonus, and ataxia. Our team has a strong track record in brining gene therapies to
the clinic and has plans to develop a gene therapy to treat sialidosis. Our previous experience has shown that
testing in large animal models of human genetic diseases better approximates what will happen and patients
and use of these models increases the likelihood of efficacy. We have developed a founder sheep with a
mutation like type 1 sialidosis patients and will breed him to generate a colony of animals. Since the last
submission we have created several severe mutations using CRISPR/spCas9 editing, therefore in this aim we will
use Prime genome editing of embryos, to recreate two human mutations (Type 1 and Type 2) with the end goal
of a mutation that recapitulates the human condition (Aim 1). We will evaluate each model for its ability to
reliably mimic sialidosis then select the best model (Aim 2). This phenotyping includes in-life clinical metrics like
MRI, EEG, EMG, neurological and cognitive testing as well as in depth post-mortem assays to determine if it
reproduces biochemical and histopathological aspects of disease. External evaluation of in-life clinical testing
will be performed by our clinical collaborator Dr. Tifft. Additionally, Dr. Tifft will make human samples available
for comparison with the new sheep model. The biochemical aspects of disease will be externally validated by
by Dr. d’Azzo (the leader in field of sialidosis) and pathological features characterized by Dr. Koehler a veterinary
neuropathologist. After completion of these studies, this fully validated model will be used to learn more about
sialidosis as a disorder, and also used in the development of an adeno associated viral gene therapy or other
future treatment strategies for sialidosis.
