Turkiye Klinikleri Pediatric Sciences - Special Topics

Pediatrik Genetikte Dun, Bugun ve Yarin Ozel Sayisi
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Lizozomal Hastalıklarda Tedavi
Treatment in Lysosomal Storage Disorders
Fatih Süheyl EZGÜa,b
aÇocuk Metabolizma Hastalıkları BD,
bÇocuk Genetik Hastalıkları BD, Gazi Üniversitesi Tıp Fakültesi, Ankara
Turkiye Klinikleri J Pediatr Sci. 2016;12(4):67-70
Article Language: TR
ÖZET
Lizozomal depo hastalıkları, lizozom içerisinde yer alan bir ya da birden fazla enzimin eksikliği ya da transport mekanizmalarındaki bozukluk sonucu gelişen kalıtsal metabolik hastalıklardır. Grup olarak doğum prevelansı yaklaşık 5000-7700'de 1 olarak bildirilmektedir. Lizozomal hastalıklarda kompleks makromolekullerin yıkımının bozulması sonucu bu moleküller ya da türevleri doku ve organlarda birikerek hücresel işlevlerin bozulmasına yol açmaktadır. Lizozomal hastalıkların klinik spektrumu oldukça değişkenlik göstermekle birlikte hemen her zaman ilerleyicidir. Organizmadaki hemen tüm organ ve dokular hedef olabilmekle birlikte özellikle merkezi sinir sistemi ana hedeftir. Özellikle son 20 yılda lizozomal hastalıkların patofizyolojisi ve tedavileri üzerine yapılan araştırmalarda çok büyük başarılar elde edilmiştir. Bu çalışmaların sonucunda bazı lizozomal hastalıklarda nedene yönelik tedavi uygulamaları kullanıma girmiştir. İlk olarak noronopatik olmayan Gaucher hastalığında kullanıma giren enzim replasman tedavisi daha sonraki donemde Mukopolisakkaridoz Tip I, II, IV ve VI ile, Pompe, Fabry ve Wolman-Kolesterol Ester Depo hastalıklarında da kullanıma girmiştir. Enzim replasman tedavisinin en büyük dezavantajı ise, kan-beyin bariyerini geçemediğinden merkezi sinir sistemi tutulumunda etkisiz kalmasıdır. Defektif metabolik yolağın, başka bir düzeyden hedefli olarak bloke edilerek toksik substratın birikimini önlemeyi amaçlayan substrat redüksiyon tedavisi ise yine noronopatik olmayan Gaucher ve Niemann-Pick Tip C hastalıklarında kullanıma girmiştir. Hematopoietik kok hücre tedavisi ise pek çok lizozomal hastalığın tedavisinde denenmiştir. Günümüzde özellikle çok erken yaşlarda tanı almış Mukopolisakkaridoz Tip I'li hastaların tedavisinde ilk seçenek olarak yer almaktadır. Krabbe hastalığı ve Met akromatik Lokodistrofi'de ise yine sıklıkla başvurulan tedavi secenekleri arasında yer almaktadır. Pek çok lizozomal hastalıkta araştırma düzeyinde tedavi çalışmaları süregelmektedir. Niemann-Pick Tip B, Alfa-mannosidozis ve Farber hastalıklarında enzim replasman tedavisi çalışmaları halen devam etmektedir. Mukopolisakkaridoz Tip IIIB ve Globoid Hücre Lokodistrofisi'nde ise intraventrikuler enzim raplasman tedavisi çalışmaları başlamıştır. Fabry hastalığı ve GM1 gangliosidozis'de missense mutasyonlar sonucu katlanması bozulmuş enzimleri yeniden aktif hale getirmeyi amaçlayan şaperon tedavisi; Mukopolisakkaridozis Tip I'de "nonsense" mutasyonlara karşı "read-through" stratejisi ve Gaucher ve Fabry hastalıklarında substrat redüksiyon tedavisi çalışmaları halen sürmektedir. Genetik hastalıkların kesin tedavileri için bir umut ışığı olmaya devam eden gen terapisi ise farklı tekniklerle Mukopolisakkaridoz Tip III A ve B, Tip VI, Metakromatik lokodistrofi ve Pompe hastalıklarında denenmektedir. Özellikle kalıtsal metabolik hastalıklar için tanı yöntemlerinde kaydedilen ilerlemeye paralel olarak büyük gelişme gösteren tedavi çalışmalarının, gelecekte lizozomal hastalıkların nedene yönelik tedavilerine büyük katkıda bulunacağını tahmin etmek güç değildir. Ancak bu hastalık grubunun takip ve tedavisinde en önemli noktalardan ikisinin de multidisipliner yaklaşım ve destekleyici tedavi olduğu unutulmamalıdır.

Anahtar Kelimeler: Lizozomal depo hastalıkları; enzim replasman tedavisi; kök hücre; gen tedavisi
ABSTRACT
Lysosomal storage diseases result from the lack of one or more enzymes or from the defects of transport mechanisms located within the lysosomes. As a group, birth prevalence is reported to be approximately 1 in 5000-7700. Mainly, the lysosomal destruction of complex macromolecules is impaired which results in accumulation of these substances in organs and tissues. Lysosomal storage diseases are almost always progressive, although variability of clinical presentation is generally observed. During the last 20 years, significant achievements in pathophysiology, diagnosis and treatment have been obtained. Initially enzyme replacement therapy was available for non-neuronopathic Gaucher Disease. Later on, enzyme replacement therapies for Mucopolysaccharidosis Types I, II, IV and VI, Pompe, Fabry and Wolman-Cholesterol Ester Storage diseases were available. The most important disadvantage of enzyme replacement therapy, is the unavailability of the enzyme molecule through the blood-brain barrier for the diseases targeting the central nervous system. Artificial blockage of a biochemical pathway at a level other than the level of the genetic defect in order to prevent the accumulation of the toxic intermediate substrate forms the basis of substrate inhibition therapy. This therapy was put into use for non-neorunopathic Gaucher and Niemann-Pick Type C diseases. Stem cell transplantation has been investigated for the treatment of many lysosomal storage disorders. Today, it is generally accepted as the first line treatment for Mucopolysaccharidosis Type I if the patients have been diagnosed at an early age and without central nervous system involvement. Krabbe disease and metachromatic leukodystrophy are the other lysosomal disorders for which stem cell transplantation has also been used. Significant number research studies have been carried out for the treatment of nearly all types of lysosomal disorders. Niemann-Pick Type B, alpha-mannosidozis and Farber are such disorders. Intratechal enzyme replacement therapy trails have been started for Mucopolysaccharidosis Type IIIB and neuronal ceroid lipofuscinosis. Chaperone therapy is aimed at restoring the enzyme activity in a disorder which results from a missense mutation that results in a misfolded enzyme. Chaperone therapy has been used for the treatment of Fabry disease as well as GM1 gangliosidosis. The hope of gene therapy still continues for disorders such as Mucopolysaccharidosis Type IIIA and B, Type VI as well as metachromatic leukodystrophy and Pompe diseases. It is obvious that better treatment options will be available for a great majority of lysosomal diseases in the near future.

Keywords: Lysosomal storage diseases; enzyme replacement therapy; stem cells; gene therapy

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