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Delivery of Therapeutic Agents Through Intracerebroventricular ICV and Intravenous IV Injection in Mice
Published on: October 3, 2011
Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular
Beltran Borges1,2,3, Stephen M Brown4, Wan-Jin Chen5,6
1Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Insights
Prenatal treatment using antisense oligonucleotides (ASOs) via intra-amniotic injection shows promise for treating spinal muscular atrophy (SMA). This approach improved outcomes in fetal mice and demonstrated safety in sheep, offering hope for early-onset neurological disorders.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Neurological disorders present at birth cause significant infant mortality and morbidity.
- Prenatal interventions can prevent irreversible neuronal damage and support neurodevelopment.
- Current postnatal treatments for spinal muscular atrophy (SMA) may not fully address severe cases.
Purpose of the Study:
- To investigate the safety and efficacy of intra-amniotic (IA) injection of antisense oligonucleotides (ASOs) for prenatal treatment of SMA.
- To assess ASO distribution to the fetal central nervous system (CNS) and therapeutic effects.
- To evaluate IA ASO delivery in a large-animal model for potential clinical translation.
Main Methods:
- ASOs were administered via IA injection into two mouse models of severe SMA.
- Therapeutic benefits were assessed through motor neuron counts, axon development, behavioral tests, and survival rates.
- IA and intracranial ASO delivery were tested in mid-gestation fetal sheep to evaluate distribution and toxicity.
Main Results:
- IA ASO injection in SMA mice increased SMN protein expression in the CNS.
- Prenatal treatment in SMAΔ7 mice improved motor neuron survival, axon development, behavior, and survival compared to postnatal treatment.
- In fetal sheep, IA ASO injection led to therapeutic concentrations in the spinal cord with no significant fetal or maternal toxicity.
Conclusions:
- IA delivery of ASOs is a potential minimally invasive strategy for prenatal treatment of SMA.
- This approach may also be applicable to other severe, early-onset neurological conditions.
- Prenatal ASO therapy offers a promising avenue to mitigate neurological deficits from birth.
Abstract:
Neurological disorders with onset before or at birth are a leading cause of morbidity and mortality in infants and children. Prenatal treatment has the potential to reduce or prevent irreversible neuronal loss and facilitate normal neurodevelopment. We hypothesized that antisense oligonucleotides (ASOs) delivered to the amniotic fluid by intra-amniotic (IA) injection could safely distribute to the fetal central nervous system (CNS) and provide therapeutic benefit in the motor neuron disease spinal muscular atrophy (SMA), caused by mutations of the survival of motor neuron 1 gene (SMN1), leading to deficiency of SMN protein. Although the splice-switching ASO nusinersen ameliorates SMA when delivered postnatally, substantial deficits can remain in severely affected infants. Here, IA injection of ASOs into two mouse models of severe SMA increased SMN expression in the CNS. In SMAΔ7 mice, which manifest pathology in utero, prenatal treatment improved motor neuron numbers, motor axon development, motor behavioral tests, and survival when compared with those in mice treated postnatally (between P1 and P3). To assess the feasibility of prenatal treatment in a large-animal model, ASOs were delivered midgestation to fetal sheep by IA or intracranial injection. ASOs delivered by IA injection distributed to the spinal cord at therapeutic concentrations and to multiple peripheral tissues without evidence of substantial toxicity to the fetus or mother. These data demonstrated that IA delivery of ASOs holds potential as a minimally invasive approach for prenatal treatment of SMA and possibly other severe, early-onset neurological disorders.
