Clinical bottom line
Gene therapy offers a transformative approach for treating inherited immunodeficiency disorders, including severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome (WAS). However, patients undergoing gene therapy remain at heightened risk of infections due to underlying immune defects, conditioning regimens, and immune reconstitution dynamics. Current evidence highlights the critical need for tailored infection surveillance, prophylaxis, and management strategies throughout the gene therapy continuum. Emerging data from newborn screening programs and advances in vector design are refining patient selection and timing, but infectious complications remain a key challenge warranting multidisciplinary vigilance.
What the evidence shows
Inherited immunodeficiency disorders such as SCID and WAS are characterized by profound defects in cellular and humoral immunity, predisposing patients to severe, recurrent infections from early life (Chinn et al., 2015; Cavannaugh et al., 2022). Gene therapy, including ex vivo hematopoietic stem cell modification and in vivo vector delivery, aims to restore immune function by correcting genetic defects (Rajapaksha et al., 2019).
Newborn screening for SCID has improved early diagnosis and facilitated timely gene therapy interventions before infectious complications become severe (Howley et al., 2024). Early treatment correlates with better immune reconstitution and reduced infection-related morbidity. However, patients with congenital athymia or complex syndromic immunodeficiencies may require additional supportive care due to persistent immune deficits (Howley et al., 2024).
The conditioning regimens used to enable engraftment of gene-corrected cells often involve chemotherapy or immunosuppressive agents, which transiently increase infection risk. Post-therapy immune reconstitution is variable and may be delayed, necessitating prolonged antimicrobial prophylaxis and close infection monitoring (Chinn et al., 2015).
Wiskott-Aldrich syndrome patients undergoing gene therapy face risks from both their baseline immunodeficiency and therapy-related immune perturbations. Advances in vector design and gene editing have improved safety profiles, but infectious complications remain a concern, requiring individualized prophylaxis and vigilance (Cavannaugh et al., 2022).
Rare inherited disorders such as Chediak-Higashi syndrome also present unique infectious risks due to defects in lysosomal trafficking and neutrophil function, underscoring the need for comprehensive infection management in gene therapy candidates (Greene et al., 2024).
Gene therapy vectors, including adeno-associated virus (AAV)-based platforms, have shown promise in delivering corrective genes with reduced immunogenicity, but vector-related immune responses and off-target effects may influence infection susceptibility (Rajapaksha et al., 2019).
Caveats and uncertainty
Most clinical experience with gene therapy in inherited immunodeficiencies derives from small cohorts and early-phase trials, limiting generalizability. Long-term infectious outcomes remain incompletely characterized, particularly regarding late immune reconstitution and secondary immunodeficiencies.
Optimal antimicrobial prophylaxis regimens, vaccination timing, and infection surveillance protocols post-gene therapy are not yet standardized and require tailoring based on individual immune recovery kinetics.
The impact of pre-existing infections or latent viral reactivations on gene therapy outcomes is not fully understood. Additionally, immune responses to gene therapy vectors may vary, influencing infection risk.
Emerging gene editing technologies and in vivo delivery methods introduce novel variables affecting immune competence and infection susceptibility, necessitating ongoing research and clinical vigilance.
How this may change practice
Clinicians should incorporate early genetic diagnosis, ideally via newborn screening, to identify candidates for gene therapy before severe infections occur, improving outcomes (Howley et al., 2024).
Multidisciplinary teams including immunologists, infectious disease specialists, and gene therapy experts are essential to optimize infection prevention, monitoring, and treatment throughout the gene therapy process.
Individualized infection prophylaxis strategies should be based on underlying disease, conditioning regimen, and immune reconstitution status, with protocols adapted as more data emerge.
Routine surveillance for viral reactivations and opportunistic infections is warranted, alongside judicious use of vaccinations timed to immune recovery milestones.
Advances in vector design and delivery may reduce infection risks, but clinicians must remain alert to vector-related immune effects and emerging infectious complications.
Ongoing collection of long-term safety and infectious outcomes data will be critical to refine clinical guidelines and improve patient care in this rapidly evolving field.