Evolution of therapy monogenic orphan diseases and regulatory aspects of orphan medicinal products development

INTRODUCTION. There are between 6,000 and 8,000 described rare (orphan) diseases worldwide, about 80% of which are genetic in origin and often life-threatening. Historically, the development of medicinal products (MPs) for RDs was hampered by a lack of economic incentives. Over the past 10 years, Russia has seen an active increase in the number of approved new MPs for RDs.

AIM. To trace the history of approaches to the treatment of the most common monogenic orphan diseases and analyze the problematic aspects of the development and implementation of orphan drugs in medical practice.

DISCUSSION. Historical examples of rare diseases illustrate both the slow progress of therapy from symptomatic to pathogenetic (cystic fibrosis) and the explosive growth of pathogenetic MPs of various modalities where no effective therapy existed before (spinal muscular atrophy). The path from symptomatic treatment and early replacement approaches to modern pathogenetic and etiotropic strategies is shown, including recombinant proteins, small molecules (potentiators and correctors), oligonucleotide-based drugs, enzyme replacement therapy, and gene therapy based on adeno-associated viral vectors. Special attention is paid to overcoming barriers such as viral safety, drug delivery across the blood-brain barrier ("Trojan horses"), and the challenges of commercializing gene therapy. The review examines current regulatory mechanisms and support measures for the development of orphan MPs in Russia, the EAEU countries, and the world.

CONCLUSIONS. The experience of recent decades indicates a transformation in the approach to rare diseases which have ceased to be "hopeless" and have become an area of the most intensive development in biomedical technologies. Further progress will be linked not only to the creation of new gene and cell therapy methods but also to the establishment of effective regulatory, economic, and social mechanisms ensuring equal patient access to therapy.

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