Journal article Open Access

A New Era in Vaccine Technology: mRNA-Based Vaccine Design

Şahiner, Fatih; Aygar, İsmail Selçuk

Özet

Messenger RNA (mRNA) teknolojisi hem genetik hastalıkların ve kanserlerin tedavisinde (terapötik kanser aşıları) hem de enfeksiyöz hastalıkların yayılımının önlenmesinde gelecek vaat eden yeni nesil bir yaklaşımı temsil eder. mRNA aşı sistemlerinin temel mantığı istenilen bir proteinin viral bir enfeksiyonu taklit ederek vücutta üretilmesini sağlamak ve onun işlevlerinden yararlanmaktır. DNA temelli sistemlerden ve viral vektörlerden farklı olarak üretilmek istenilen proteine ait genetik kodu taşıyan mRNA molekülleri ikinci bir aracı genetik sistem olmaksızın hücrelere doğrudan iletilir ve protein üretimi için gönderilen mesajın sitoplazmaya ulaşması yeterli olduğundan bu moleküller kromozomal yapılara entegre olma riski taşımazlar. mRNA temelli sistemlerin tasarlanmasındaki temel zorluklar bu moleküllerin hücre içi ve hücre dışı enzimlere çok duyarlı olması, stabilizasyon sorunları, doğal immün sistem tarafından tanınarak ortadan kaldırılması gibi sınırlayıcı özelliklerdir. Tüm bu problemlerin üstesinden gelmek ve başarılı mRNA transfeksiyonu elde etmek adına kapak analogları, modifiye nükleotidler, genetik sekans mühendisliği müdahaleleri, taşıyıcı partiküller ve oda sıcaklığına dayanıklı mRNA sistemlerinin geliştirilmesine yönelik alanlarda son 10 yılda önemli ilerlemeler kaydedilmiştir. Bir diğer önemli nokta ise mRNA sistemlerinin immünojenisitesinin optimize edilmesidir; istenilen adjuvan benzeri etkileri belirli bir derecede korurken, otoimmünite veya aşırı duyarlılık reaksiyonlarına neden olabilecek antijenik uyarılardan kaçınma arasındaki dengeyi sağlamak önemlidir. Bu amaçla özel saflaştırma yöntemlerinin seçimi ve ökaryotik mRNA’lara benzer motiflerin kullanılması gibi yaklaşımlar ve ek adjuvanlarla beraber kullanılan sistemler tasarlanmıştır. Replike olabilen mRNA sistemleri adjuvan özelliği sergileyen çift zincirli RNA (dsRNA) gibi kendi adjuvanlarını üretebilmesi ve daha uzun süreli antijen üretimi ile farklı amaçlara yönelik yeni ve düşük üretim maliyetli tasarım sistemleri olarak denenmektedir. Aynı mRNA molekülü üzerinden birden fazla antijenin veya proteinin hücresel ekspresyonu gibi esnek seçenekler de denenmiştir. Bu makalede mRNA temelli sistemlerin alternatif tasarımlarına değinilmiş ve mRNA aşı teknolojisindeki son gelişmelerin bir özeti sunulmuştur.

Abstract

Messenger RNA (mRNA) technology represents a promising next-generation approach to both the treatment of genetic diseases and cancers (therapeutic cancer vaccines) and the prevention of the spread of infectious diseases. The basic principle of mRNA vaccine systems is to ensure that a desired protein is produced in the body by mimicking a viral infection and to benefit from its functions. Unlike DNA-based systems and viral vectors, mRNA molecules carrying the genetic code of the desired protein to be produced are directly transmitted to the cells without a second intermediary genetic system, and these molecules do not have the risk of integrating into chromosomal structures, since it is enough for the message sent to reach the cytoplasm for protein production. The main difficulties in designing mRNA-based systems are the limiting features of these molecules, such as being very sensitive to intracellular and extracellular enzymes, stabilization problems, and eliminating them by being recognized by the innate immune system. In order to overcome all these problems and achieve successful mRNA transfection, significant progress has been made in the last 10 years in the fields of cap analogs, modified nucleotides, genetic sequence engineering interventions, carrier particles and the development of room temperature resistant mRNA systems. Another important point is optimizing the immunogenicity of mRNA systems; the balance between avoiding antigenic stimuli that can cause autoimmunity or hypersensitivity reactions and maintaining a certain degree of desired adjuvant-like effects is important. For this purpose, approaches such as the selection of special purification methods and the use of motifs similar to eukaryotic mRNAs and systems used with additional adjuvants have been designed. Self-amplifying mRNA systems are being tested as new and low production cost design systems for different purposes with the ability to produce their own adjuvants, such as double strand RNA (dsRNA) that exhibit adjuvant properties, and with longer antigen production. In this article, alternative designs of mRNA-based systems are discussed and a summary of recent developments in mRNA vaccine technology is presented.

Aşı Teknolojisinde Yeni Bir Dönem: mRNA Temelli Aşı Tasarımı
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