The Impact of Genomic Variations Detected by NGS on Treatment, Treatment Outcomes, and Clinical Parameters in Patients with PNH

Project no. 31883 · Status: Kapanmış (Yayın bekleniyor) · 2024

Summary

<p>Paroxysmal&nbsp;Nocturnal&nbsp;Hemoglobinuria&nbsp;(PNH)&nbsp;is&nbsp;an&nbsp;ultra-rare&nbsp;stem&nbsp;cell&nbsp;disorder&nbsp;characterized&nbsp;by&nbsp;bone&nbsp;marrow&nbsp;failure,&nbsp;signs&nbsp;of&nbsp;non-immune&nbsp;intravascular&nbsp;hemolysis,&nbsp;and&nbsp;a&nbsp;clinical&nbsp;picture&nbsp;of&nbsp;thrombosis.&nbsp;PNH&nbsp;is&nbsp;a&nbsp;rare&nbsp;form&nbsp;of&nbsp;acquired&nbsp;hemolytic&nbsp;disorder,&nbsp;typically&nbsp;characterized&nbsp;by&nbsp;episodes&nbsp;of&nbsp;intravascular&nbsp;hemolysis&nbsp;and&nbsp;hemoglobinuria.&nbsp;PNH&nbsp;is&nbsp;a&nbsp;genetic&nbsp;disorder&nbsp;caused&nbsp;by&nbsp;a&nbsp;deficiency&nbsp;of&nbsp;the&nbsp;glycophosphatidylinositol&nbsp;(GPI)&nbsp;protein&nbsp;in&nbsp;red&nbsp;blood&nbsp;cells.</p><p></p><p>Clinical&nbsp;laboratory&nbsp;tests&nbsp;used&nbsp;for&nbsp;PNH&nbsp;diagnosis&nbsp;include&nbsp;a&nbsp;complete&nbsp;blood&nbsp;count&nbsp;(CBC),&nbsp;peripheral&nbsp;blood&nbsp;smear,&nbsp;absolute&nbsp;reticulocyte&nbsp;count,&nbsp;indirect&nbsp;bilirubin,&nbsp;LDH,&nbsp;haptoglobin,&nbsp;and&nbsp;Coombs&nbsp;test,&nbsp;all&nbsp;of&nbsp;which&nbsp;provide&nbsp;laboratory&nbsp;findings&nbsp;related&nbsp;to&nbsp;hemolysis&nbsp;(the&nbsp;breakdown&nbsp;of&nbsp;red&nbsp;blood&nbsp;cells).&nbsp;In&nbsp;addition,&nbsp;the&nbsp;High-Sensitivity&nbsp;Flow&nbsp;Cytometry&nbsp;method—considered&nbsp;the&nbsp;gold&nbsp;standard&nbsp;for&nbsp;PNH&nbsp;diagnosis—is&nbsp;used&nbsp;to&nbsp;demonstrate&nbsp;the&nbsp;absence&nbsp;of&nbsp;GPI&nbsp;anchor&nbsp;proteins&nbsp;in&nbsp;peripheral&nbsp;blood&nbsp;samples,&nbsp;and&nbsp;a&nbsp;bone&nbsp;marrow&nbsp;examination&nbsp;is&nbsp;performed.</p><p></p><p>Considering&nbsp;the&nbsp;tests&nbsp;performed&nbsp;at&nbsp;the&nbsp;clinic,&nbsp;the&nbsp;current&nbsp;testing&nbsp;protocol&nbsp;does&nbsp;not&nbsp;include&nbsp;genomic&nbsp;analysis.&nbsp;In&nbsp;addition&nbsp;to&nbsp;these&nbsp;clinical&nbsp;tests,&nbsp;the&nbsp;presence&nbsp;of&nbsp;any&nbsp;genomic&nbsp;mutations&nbsp;in&nbsp;patients&nbsp;is&nbsp;thought&nbsp;to&nbsp;potentially&nbsp;influence&nbsp;the&nbsp;course&nbsp;of&nbsp;the&nbsp;disease&nbsp;and&nbsp;the&nbsp;patients’&nbsp;positive&nbsp;or&nbsp;negative&nbsp;response&nbsp;to&nbsp;the&nbsp;monoclonal&nbsp;antibody&nbsp;therapy&nbsp;used&nbsp;in&nbsp;routine&nbsp;treatment.</p><p></p><p>In&nbsp;this&nbsp;context,&nbsp;the&nbsp;project&nbsp;we&nbsp;propose&nbsp;aims&nbsp;to&nbsp;perform&nbsp;Whole&nbsp;Exome&nbsp;Sequencing&nbsp;(WES)&nbsp;and&nbsp;transcriptome&nbsp;analysis&nbsp;(mRNA&nbsp;sequencing)&nbsp;in&nbsp;patients&nbsp;using&nbsp;Next-Generation&nbsp;Sequencing&nbsp;(NGS).</p><p>A&nbsp;review&nbsp;of&nbsp;the&nbsp;literature&nbsp;revealed&nbsp;some&nbsp;sequencing&nbsp;studies&nbsp;related&nbsp;to&nbsp;this&nbsp;disease;&nbsp;however,&nbsp;none&nbsp;of&nbsp;these&nbsp;studies&nbsp;have&nbsp;been&nbsp;linked&nbsp;to&nbsp;or&nbsp;interpreted&nbsp;in&nbsp;relation&nbsp;to&nbsp;the&nbsp;two&nbsp;different&nbsp;monoclonal&nbsp;antibody&nbsp;therapies&nbsp;(eculizumab,&nbsp;ravulizumab)&nbsp;that&nbsp;patients&nbsp;use&nbsp;in&nbsp;routine&nbsp;treatment.</p>

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