Document text
Principal Investigator: David E. Pleasure
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2023
Award: $423,939
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
Canavan disease is a rare genetic neurological disorder characterized by a vacuolar (spongiform)
leukodystrophy caused by ASPA mutations that diminish brain aspartoacylase activity.
Neonatal/infantile Canavan disease is the most common and most severe form of the condition.
Affected infants appear normal for the first few months of life, but problems with development become
noticeable by age 3 to 5 months. These infants usually do not develop motor skills such as turning over,
controlling head movement, and sitting without support. Other characteristics of this condition include
hypotonia, macrocephaly, and irritability. There is no cure, nor is there a standard course of treatment.
The symptomatic support for this neurodegenerative disorder includes dietary manipulations,
administration of lithium citrate and anticonvulsants, and AAV-mediated brain parenchymal ASPA gene
therapy, yet, these treatments do not reverse or prevent the progression of neurological deficits in
affected infants and children. To address this unmet medical need, we propose to develop an innovative
treatment comprised of an in utero delivery of solid lipid nanoparticle (LNP)/mRNA complexes by
intraventricular injection that will target and edit oligodendrocyte before birth, correct ASAP mutations,
and restore aspartoacylase expression in patients influenced by point mutations. Gene editing at the in
utero stage has great potential to cure neurological disorders, including Canavan disease before
symptoms are unset. Our preliminary studies demonstrated that in utero intraventricular delivery LNP
mRNA complexes can efficiently deliver mRNA to the brain and spinal cord tissue. These experiments
are the first demonstration of mRNA based nonviral gene editing in utero and open up numerous
therapeutic applications, given the tremendous versatility of mRNA. The central hypothesis of this
proposal is that: LNPs will deliver mRNA for gene editing enzymes in utero and will rescue mice from
Canavan disease at and after birth. This hypothesis is based upon our preliminary data demonstrating
that LNPs containing CRE can safely and efficiently transfect oligodendrocyte in the brain of Ai9 mice
after in utero intraventricular delivery. The central objective of this study is to develop LNP formulations
that can efficiently edit oligodendrocyte in utero and develop a strategy for treating Canavan disease.
Terms: <0-11 years old><Address><Affect><Age><Age Months><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><Aspartoacylase><Aspartoacylase Deficiency Disease><Birth><Body Tissues><Brain><Brain Nervous System><CNS Diseases><CNS disorder><Canavan Disease><Canavan-van Bogaert-Bertrand Disease><Caring><Cell Body><Cells><Central Nervous System Diseases><Central Nervous System Disorders><Characteristics><Child><Child Youth><Children (0-21)><Citrates><Clinical><Complex><DNA Alteration><DNA Sequence Alteration><DNA Therapy><DNA mutation><Data><Decreased Muscle Tone><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Disease><Disorder><Electroporation><Encapsulated><Encephalon><Enzyme Gene><Enzymes><Fetal Therapies><Fetus><Formulation><Gene Transfer Clinical><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Intervention><Genetic defect><Genetic mutation><Genome><Goals><Guide RNA><Head Movements><Healthcare><Hospitals><Hour><Hypomyotonia><Hypotonia><Immune system><In Vitro><Incidence><Infant><Injections><Intraventricular><Intraventricular Injections><Jewish><Judaism><Li+ element><Life><Lipids><Lithium><Macrocephaly><Mediating><Medical><Medulla Spinalis><Megacephaly><Megalocephaly><Messenger RNA><Methods><Mice><Mice Mammals><Molecular Diagnosis><Motor><Motor Skills><Murine><Mus><Muscle Hypotony><Muscle Tone Poor><Muscle hypotonia><Muscular Hypotonia><Mutation><N-acetylaspartic acid><N-acyl-L-aspartate amidohydrolase><Neonatal><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurodevelopmental Disorder><Neurologic Deficit><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Development Disorder><Neurological Disorders><Non-Polyadenylated RNA><Non-Viral Vector><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Onset of illness><Other Genetics><Parturition><Patients><Phenotype><Point Mutation><Population><Progenitor Cells><Proliferating><Proteins><RNA><RNA Gene Products><Reagent><Ribonucleic Acid><Safety><Sequence Alteration><Solid><Spinal Cord><Spongiform Leukodystrophy><Spongy Degeneration of Infancy><Spongy Disease of Central Nervous System><Spongy Disease of White Matter><Symptoms><System><Technology><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Transfection><Treatment Cost><ages><alleviate symptom><ameliorating symptom><aminoacylase II><autosome><base><base editor><bases><brain cell><carrier detection><carrier screening><carrier testing><decrease symptom><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><dietary manipulation><disease onset><disorder onset><electroporative delivery><enzyme activity><experiment><experimental research><experimental study><experiments><fetal><fetus therapy><fewer symptoms><follower of religion Jewish><functional outcomes><gRNA><gene electrotransfer><gene repair therapy><gene therapy><gene-based therapy><genetic condition><genetic disorder><genetic therapy><genome editing><genome mutation><genomic alteration><genomic editing><genomic therapy><health care><in utero><in utero therapy><infancy><infantile><innovate><innovation><innovative><kids><leukodystrophy><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><mouse model><murine model><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nervous system disorder><neurodegenerative illness><neurodevelopmental disease><neurological disease><nonviral vector><obstetric care><population based><prenatal><prenatal therapy><prevent><preventing><prime editing><prime editor><progenitor><reduce symptoms><relieves symptoms><seizure drug><seizure medication><stem><stem cells><symptom alleviation><symptom reduction><symptom relief><technology platform><technology system><unborn><youngster>