Abstract Details

Title A Novel Mouse Model with Tubb4a (D249N/D249N) for classical Hypomyelination and atrophy of basal ganglia and cerebellum

Topic Child Neurology and Developmental Neurology

Presentation(s) S51 - Child Neurology: Bench to Bedside: Progress in Treating Genetic Disorders (4:36 PM-4:47 PM)

Poster/Presentation
Number 007

Background H-ABC is part of a spectrum of hypomyelinating leukodystrophies caused by mutations in the gene encoding tubulin alpha 4 (TUBB4A). Disease onset begins in early childhood characterized by dystonia, ataxia, altered gait and progressive motor decline. The most common identified mutation is p.Asp249Asn (D249N), seen in over 30% of individuals with TUBB4A mutations, and nearly all individuals with the canonical H-ABC presentation. To date, there is no therapeutic approach available for H-ABC.

Objective We propose a novel murine model for Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC).

Design/Methods We developed a knock-in mouse model harboring homozygous (Tubb4a^D249N/D249N) TUBB4A mutations using a CRISPR-Cas9 approach. This model underwent comprehensive behavioral phenotyping as well as detailed histologic and ultramicroscopic analysis. Analysis was compared to wild-type littermates.

Results We report the first mouse model of classical H-ABC (Tubb4a^D249N/D249N), which displays disease onset in the first 2 weeks of life (PND,9.8 ± 0.472, n=10), decreased survival (PND,37.48 ± 3.72, n=27), progressive tremor, abnormal gait and dystonia, as well as hypomyelination, cerebral atrophy and striatal cellular loss, thus recapitulating the phenotypic features of the disease. Neuropathological assessment of Tubb4a^D249N/D249Nmice on PND 21 and end-stage PND 40 shows decreased myelin staining in corpus callosum and drastic loss of neurons in striatum and cerebellum (p<0.0001). The immunolabelling at PND 21 and end-stage reveal dramatic loss of ASPA positive oligodendrocytes (p<0.0001). Ultrathin brain sections for electron microscopy further demonstrated severe loss of myelin in spinal cord and optic nerve of thesemice.

Conclusions Ongoing studies are focused on understanding the mechanism of Tubb4a mutation mediated effects with respect to cell-autonomous versus non-cell-autonomous effects on oligodendrocyte and neurons. The Tubb4a^D249N/D249Nmouse provides a novel model for H-ABC, and establishes histologic and behavioral features of disease in this model which can be assessed in pre-clinical therapeutic studies.

Authors/Disclosures
Sunetra Sase, PhD (Children's hospital of Philadelphia) PRESENTER	No disclosure on file
Akshata Almad, PhD (Children'S Hospital of Philadelphia)	No disclosure on file
Asako Takanohashi, PhD, DVM (Children's Hospital of Philadelphia)	Dr. Takanohashi has nothing to disclose.
	No disclosure on file
	No disclosure on file
Steven Scherer, MD	Dr. Scherer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pfizer. Dr. Scherer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Scherer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Toray Industries. Dr. Scherer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. Dr. Scherer has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Disarm Therapeutics. Dr. Scherer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitochondria in Motion. The institution of Dr. Scherer has received research support from NIH .
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia)	An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.

��ɫ��

��ɫ��