The gene therapy journey for hemophilia: are we there yet?

Abstract

<jats:title>Abstract</jats:title><jats:p>Since the isolation and characterization of the genes for FVIII and FIX some 30 years ago, a longstanding goal of the field has been development of successful gene therapy for the hemophilias. In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno-associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of &gt; 2 years. This review discusses obstacles that were overcome to reach this goal and the next steps in clinical investigation. Safety issues that will need to be addressed before more widespread use of this approach are discussed. Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed.</jats:p>

Engraftment of a Galactose Receptor Footprint onto Adeno-associated Viral Capsids Improves Transduction Efficiency

“…The ultimate goal of such efforts is to continue to improve AAV vector technology that would help decrease the effective vector dose required for achieving therapeutically relevant transgene expression levels. These technological advancements are also likely to help alleviate potential clinical concerns associated with vector dosedependent toxicity (38,39). In summary, rational engineering of capsid-glycan receptor interactions is a promising approach toward continued improvement of the preclinical/clinical pipeline of AAV vectors for gene therapy.…”

Postępy w leczeniu chorych na hemofilie

“…[14] oraz rozszerzenia wskazań do terapii genowej hemofilii B o pacjentów zakażonych ludzkim wirusem niedoboru odporności (HIV, human immunodeficiency virus) i wirusem wątroby typu C (HCV, hepatitis C virus) oraz tych, u których wykryto przeciwciała przeciwko AAV. W ostatnim przypadku rozwiązaniem może być zastosowanie pustych kapsydów AAV2, które chronią kapsydy AAV8 zawierające gen kodujący FIX, poprzez związanie obecnych w krwiobiegu pacjenta przeciwciał przeciwko AAV [15].…”

“…Bardzo interesujące są też badania nad alternatywnymi wektorami, na przykład lentiwirusowymi. Kolejnym krokiem w rozwoju badań nad terapią genową powinno być zapoczątkowanie prób klinicznych u pacjentów z hemofilią A. Niestety, dziś wiadomo, że o sukces w terapii genowej hemofilii A będzie znacznie trudniej niż w hemofilii B -przede wszystkim z powodu wielkości cDNA FVIII oraz silniej odpowiedzi immunologicznej ludzkiego organizmu wobec FVIII [14].…”

Immunology: Oral solutions

“…Using the standard gene-therapy approach, researchers have shown that they can achieve long-term expression of factor IX in adults with haemophilia B at sufficiently high levels to convert the bleeding disorder into a mild disease (see page S160). There has so far been no reported evidence of inhibitor formation in the small number of human participants in clinical trials for this viral therapy 6 . Still, the standard form of liver-targeted gene therapy carries a range of potential complications, including the risk of harmful mutations and of the body mounting an immune response against the viral vectors used to carry the correct forms of the defective genes responsible for haemophilia.…”