LATEST ADVANCES FOR TREATING CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-HYDROXYLASE DEFICIENCY

Abstract

Congenital adrenal hyperplasia (CAH) is a group of inherit ed diseases characterised by disrupted glucocorticoid (GC) and mineralocorticoid (MC) synthesis in the adrenal glands. Most cases are caused by 21-hydroxylase (21-OH) enzyme de ficiency, which leads to diminished cortisol and aldosterone levels, a reactional increase in adrenocorticotropic hormone (ACTH), resulting in excessive adrenal androgen production. CAH is a challenging condition that often requires supraphys iological doses of GCs to suppress ACTH and subsequent androgen production. It can lead to complications such as short stature and premature puberty during childhood, hy perandrogenism, infertility, and iatrogenic Cushing syndrome in adulthood. This manuscript reviews the current therapeutic landscape, unmet needs, and emerging therapies for CAH, including corticotropin-releasing factor type 1 (CRF1) recep tor antagonists, ACTH inhibitors, and investigational gene therapies to replace 21-OH enzymatic activity. The main fo cus of the pipeline agents is to reduce androgen levels and the need for supraphysiological dosing of GCs. Crinecerfont, a CRF1 receptor antagonist, has recently been approved by the Food and Drug Administration (FDA) after showing sig nificant improvements in androgen levels in adults and pae diatric patients aged 4 years and older with classic CAH. The manufacturer claims it is the first novel CAH treatment in 70 years. However, it failed to maintain low androgen levels while reducing GC dosing. Hence, further pipeline is investi gating whether it is possible to achieve both goals or cure the disease. The long-term safety and efficacy of these promising therapeutic approaches require further investigation and elu cidation.

Keywords

• Congenital Adrenal Hyperplasia
• 21-Hydroxy lase
• Melanocortin Type 2 Receptor
• CRF Receptor Type 1
• Genetic Therapy

21-HİDROKSİLAZ EKSİKLİĞİNE BAĞLI KONJENİTAL ADRENAL HİPERPLAZİ TEDAVİSİNDEKİ YENİLİKLER

Abstract

Konjenital adrenal hiperplazi (KAH), adrenal bezlerde glukokor tikoid (GC) ve mineralokortikoid (MC) sentezinin bozulmasıyla karakterize bir grup kalıtsal hastalığı ifade eder. Vakaların büyük çoğunluğu, kortizol ve aldosteron seviyelerinin azalmasına yol açan, buna bağlı olarak adrenokortikotropik hormon (ACTH) düzeylerinde reaktif bir artışla adrenal androjen üretiminin faz laca artmasına neden olan 21-hidroksilaz (21-OH) enziminin ek sikliğinden kaynaklanır. KAH, genellikle ACTH’yi ve buna bağlı androjen üretimini baskılamak için fizyolojik sınırların üzerinde GC dozlarının kullanımını gerektiren, yönetimi zor bir hastalıktır. Bu durum, çocukluk döneminde kısa boy ve erken ergenlik, ye tişkinlikte ise hiperandrojenizm, infertilite ve iyatrojenik Cushing sendromu gibi komplikasyonlara yol açabilir. Bu makale, KAH için mevcut tedavi seçeneklerini, tedavi alanındaki eksiklikleri ve gelişmekte olan yeni tedavi yaklaşımlarını kapsamlı bir şekil de ele almaktadır. Bunlar arasında kortikotropin salıcı faktör tip 1 (CRF1) reseptör antagonistleri, ACTH inhibitörleri ve 21-OH enzimatik aktivitesini yerine koymayı hedefleyen deneysel gen tedavileri bulunmaktadır. Yeni geliştirilen ajanların ana hedefi, androjen seviyelerini azaltmak ve suprafizyolojik GC dozlarına duyulan ihtiyacı en aza indirmektir. CRF1 reseptör antagonis ti olan crinecerfont, androjen seviyelerinde önemli iyileşmeler göstermesi nedeniyle; 4 yaş ve üzeri çocuk ve yetişkin klasik KAH hastalarında kısa bir süre önce Amerikan Gıda ve İlaç Dai resi (FDA) tarafından onaylanmıştır. Üretici firma, bu ilacın son 70 yıl içerisinde onaylanan ilk yenilikçi KAH tedavisi olduğunu öne sürmektedir. Ancak, bu tedavi yöntemi, GC dozlarını azaltırken düşük androjen seviyelerini sürdürebilme hedefini karşılayamamıştır. Bu nedenle, güncel araştırmalar, her iki hedefe aynı anda ulaşılıp ulaşılamayacağı veya hastalığın tamamen tedavi edilip edilemeyeceği sorularına yanıt aramaktadır. Bu umut verici te davi yaklaşımlarının uzun vadeli güvenliği ve etkinliği daha fazla araştırma ile kapsamlı bir şekilde değerlendirilmelidir.

Keywords

• Konjenital Adrenal Hiperplazi
• 21-Hidroksi laz Eksikliği
• Melanokortin Tip 2 Reseptörü
• Kortikotropin Salgı latıcı Faktör
• genetik tedavi

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