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Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex
Stefanie Anderl1, Megan Freeland, David J Kwiatkowski
1Division of Translational Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
Insights
Prenatal rapamycin therapy shows promise for treating tuberous sclerosis complex (TSC) by reducing mTOR pathway hyperactivation in a fetal brain model. However, limitations exist, including developmental delays in surviving mice.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Infantile spasms and developmental consequences are common in tuberous sclerosis complex (TSC) due to early-onset epilepsy.
- TSC brain pathology, including cortical tubers, develops late in gestation.
- A fetal brain model of TSC is crucial for studying prenatal interventions.
Purpose of the Study:
- To investigate the therapeutic potential of prenatal rapamycin in a mouse model of TSC.
- To assess the effects of prenatal rapamycin on mTOR pathway hyperactivation and survival in TSC.
- To evaluate the long-term benefits and limitations of prenatal rapamycin for TSC.
Main Methods:
- Utilized a Tsc1(cc) Nes-cre(+) mouse model where Tsc1 loss in neural progenitors mimics TSC.
- Administered a single dose of prenatal rapamycin (1 mg/kg, subcutaneous) to pregnant dams.
- Assessed mTOR pathway activity, survival rates, and neurodevelopmental outcomes in mutant mice.
Main Results:
- Prenatal rapamycin administration rescued neonatal lethality in Tsc1 mutant mice.
- A single prenatal dose reduced mTOR hyperactivation in the mutant brain without adverse effects on pregnancy.
- Postnatal rapamycin extended survival, but treated mutants exhibited enlarged brains, increased cell numbers, runting, and developmental delay.
Conclusions:
- Prenatal rapamycin demonstrates therapeutic benefits for TSC by targeting mTOR hyperactivation in a prenatal-onset model.
- Limitations include persistent developmental delays and brain abnormalities despite treatment.
- Findings suggest potential but also highlight challenges for prenatal rapamycin therapy in TSC infants.
Abstract:
Epileptic seizures, particularly infantile spasms, are often seen in infants with tuberous sclerosis complex (TSC) soon after birth. It is feared that there are long-term developmental and cognitive consequences from ongoing, frequent epilepsy. In addition, the hallmark brain pathology of TSC, cortical tubers and giant cells are fully developed at late gestational ages. These observations have led us to examine the benefit of prenatal rapamycin in a new fetal brain model of TSC. In this Tsc1(cc) Nes-cre(+) mouse model, recombination and loss of Tsc1 in neural progenitor cells leads to brain enlargement, hyperactivation of mTOR, and neonatal death on P0 due to reduced pup-maternal interaction. A single dose of prenatal rapamycin given to pregnant dams (1 mg/kg, subcutaneous) rescued the lethality of mutant mice. This one dose of prenatal rapamycin treatment reduced hyperactivation of the mTOR pathway in the mutant brain without causing apparent pregnancy loss. Continued postnatal rapamycin beginning at day 8 extended the survival of these mice to a median of 12 days with complete suppression of hyperactive mTOR. However, the rapamycin-treated mutants developed enlarged brains with an increased number of brain cells, displaying marked runting and developmental delay. These observations demonstrate the therapeutic benefit and limitations of prenatal rapamycin in a prenatal-onset brain model of TSC. Our data also suggest the possibility and limitations of this approach for TSC infants and mothers.
