IMMUNOLOGICAL ASPECTS OF GENE THERAPY: BARRIERS AND WAYS TO OVERCOME

Abstract

The article discusses the key immunological mechanisms that limit the effectiveness and safety of gene therapy using viral and non-viral delivery platforms. It has been shown that the clinical outcome is determined not only by the accuracy of the transfer or editing of genetic material, but also by the nature of the interaction between the vector, the target tissue and the patient's immune system. The greatest attention is paid to the innate recognition of vectors, complement activation, production of pro-inflammatory cytokines, pre-existing neutralizing antibodies, the T-cell response to the capsid, and the problem of the immune response to the transgene product.

The limitations of repeated dosing, the differences between systemic in vivo and ex vivo approaches, as well as the value of the dose, route of administration, and degree of purification of the drug are discussed separately.

The model obtained in the study showed that the respondents consider pre-existing neutralizing antibodies, T-cell damage to the transduced cells and excessive activation of innate inflammation to be the most significant barriers. Capsid engineering, pre-serological screening, individualized immunomodulation, and expansion of ex vivo strategies dominate among the most sought-after coping methods.

It is concluded that reducing the immunogenicity of gene therapy requires not one universal measure, but a combination of bioengineering vector optimization, competent stratification of patients, laboratory immune-monitoring and organizational implementation of such technologies through specialized centers.