RESUMEN

In utero gene editing (IUGE) is a potential treatment for inherited diseases that cause pathology before or soon after birth. Preexisting immunity to adeno-associated virus (AAV) vectors and Cas9 endonuclease may limit postnatal gene editing. The tolerogenic fetal immune system minimizes a fetal immune barrier to IUGE. However, the ability of maternal immunity to limit fetal gene editing remains a question. We investigated whether preexisting maternal immunity to AAV or Cas9 impairs IUGE. Using a combination of fluorescent reporter mice and a murine model of a metabolic liver disease, we demonstrated that maternal anti-AAV IgG antibodies were efficiently transferred from dam to fetus and impaired IUGE in a maternal titer-dependent fashion. By contrast, maternal cellular immunity was inefficiently transferred to the fetus, and neither maternal cellular nor humoral immunity to Cas9 impaired IUGE. Using human umbilical cord and maternal blood samples collected from mid- to late-gestation pregnancies, we demonstrated that maternal-fetal transmission of anti-AAV IgG was inefficient in midgestation compared with term, suggesting that the maternal immune barrier to clinical IUGE would be less relevant at midgestation. These findings support immunologic advantages for IUGE and inform maternal preprocedural testing protocols and exclusion criteria for future clinical trials.

Asunto(s)

Dependovirus , Edición Génica , Animales , Femenino , Dependovirus/genética , Dependovirus/inmunología , Ratones , Embarazo , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/genética , Inmunoglobulina G/sangre , Proteína 9 Asociada a CRISPR/genética , Proteína 9 Asociada a CRISPR/inmunología , Vectores Genéticos/inmunología , Intercambio Materno-Fetal/inmunología , Intercambio Materno-Fetal/genética , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Sistemas CRISPR-Cas , Feto/inmunología , Inmunidad Materno-Adquirida/inmunología

RESUMEN

ABSTRACT: In utero hematopoietic cell transplantation is an experimental nonmyeloablative therapy with potential applications in hematologic disorders, including sickle cell disease (SCD). Its clinical utility has been limited due to the early acquisition of T-cell immunity beginning at ∼14 weeks gestation, posing significant technical challenges and excluding treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days postcoitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable with that of the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T-cell depletion followed by central tolerance induction confirmed by donor-specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrated the successful application of this approach in the Townes mouse model of SCD. These findings confirm the developing fetal T-cell response as a barrier to LGT and support transient T-cell depletion as a safe and effective immunomodulatory strategy to overcome it.

Asunto(s)

Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Embarazo , Tolerancia Inmunológica , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/terapia , Complejo CD3/inmunología , Anticuerpos Monoclonales/uso terapéutico , Linfocitos T/inmunología , Humanos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Supervivencia de Injerto/inmunología , Inmunomodulación , Tolerancia al Trasplante/inmunología

Asunto(s)

Atención Prenatal , Embarazo , Femenino , Humanos , Porcinos , Animales , Animales Recién Nacidos

RESUMEN

Significant advances in maternal-fetal medicine and gene sequencing technology have fostered a new frontier of in utero molecular and cellular therapeutics, including gene editing, enzyme replacement therapy, and stem cell transplantation to treat single-gene disorders with limited postnatal treatment strategies. In utero therapies take advantage of unique developmental properties of the fetus to allow for the correction of monogenic disorders before irreversible disease pathology develops. While early preclinical studies in animal models are encouraging, more studies are needed to further evaluate their safety and efficacy prior to widespread clinical use.

Asunto(s)

Terapias Fetales , Trasplante de Células Madre Hematopoyéticas , Embarazo , Femenino , Animales , Humanos , Terapia Genética , Trasplante de Células Madre , Feto

RESUMEN

Precision medicine is an approach to medical treatment and prevention that takes into account individual variability in genes, environment, and lifestyle and allows for personalization that is based on factors that may affect the response to treatment. Several genetic and epigenetic risk factors have been shown to increase susceptibility to late-onset Alzheimer's disease (AD). As such, it may be beneficial to integrate genetic risk factors into the AD prevention approach, which in the past has primarily been focused on universal risk-reduction strategies for the general population rather than individualized interventions in a targeted fashion. This review discusses examples of a "one-size-fits-all" versus clinical precision medicine AD prevention strategy, in which the precision medicine approach considers two genes that can be commercially sequenced for polymorphisms associated with AD, apolipoprotein E (APOE), and methylenetetrahydrofolate reductase (MTHFR). Comparing these two distinct approaches provides support for a clinical precision medicine prevention strategy, which may ultimately lead to more favorable patient outcomes as the interventions are targeted to address individualized risks.