Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia

Abstract

Replacement therapy of the deficient coagulation factor using plasmaderived or recombinant concentrates is the mainstay of treatment for patients with haemophilia A and B, the most severe bleeding disorders. 1 Significant improvements have been achieved through the production of novel extended half-life products or non-replacement therapies. 2 These new drugs could overcome current prophylaxis limitations by reducing dosing frequency and changing the routes of administration (from intravenous infusions to subcutaneous injections), thereby improving compliance and rendering therapy less distressing for the patient. 3 A definitive cure for haemophilia may lie in gene therapy.Haemophilia A and B are an ideal target for gene therapy because both are monogenic disorders caused by genetic defects in the F8 and F9 genes, respectively. In addition, a modest increase in clotting factor activity (>1 IU/dL) can substantially attenuate bleeding risk, and even treatment efficacy can be assessed easily by routine laboratory assay. AbstractGene therapy is rapidly becoming a new therapeutic strategy for haemophilia A and B treatment. In the 1990s, studies in animal models showed that adeno-associated vectors (AAV) exhibited an efficient expression of factor IX (FIX). In the first clinical trial in patients with haemophilia B, therapeutic levels of FIX were documented but the expression remained only for few weeks. Subsequently, improvements in vector design, such as the use of different AAV serotypes, the development of the self-complementary vector, the engineering of the transgene with codon optimization and liver-specific expression cassette resulted in circulating FIX level between 2% and 5% for long-lasting period. Recently, a natural gain of function FIX variant (Padua) inserted in the F9 cDNA improved the expression of FIX achieving a level of more than 30% resulting in cessation of infusions and in a greatly reduction of bleeding events.Encouraging clinical progresses have been also obtained from trials of gene therapy for haemophilia A. Transgene expression persisted for three years with circulating FVIII activity levels of 52.3% in patients treated with AAV vector containing a codonoptimized F8 cDNA. A complication, reported in both clinical trials for haemophilia A and B, was the elevation of liver enzymes, which resolved with steroid treatment in a large group of patients. However, to date, the pathophysiological mechanism for the liver toxicity remains still unclear. Clinical trials with adeno-associated vectors have documented a significant success for haemophilia gene therapy demonstrating potential to transform haemophilia treatment offering hope for a long-term expression. K E Y W O R D Sadeno-associated virus, clinical trials, factor IX, factor VIII, gene therapy, haemophilia

The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression

“…[1][2][3] Gene therapy is a new approach for the treatment of HA, which may provide a cure for the disease if successful. [4][5][6] Data from ongoing clinical trials using adeno-associated virus (AAV)-mediated liver-directed FVIII expression are very encouraging. 7 However, children and adults with severe liver disease or antibodies against AAV, which are present in 40% to 50% of the population, are excluded from AAV-mediated liver-directed gene therapy.…”

AAV9-Retro Mediates Efficient Transduction with Axon Terminal Absorption and Blood-brain Barrier Transportation

“…Adeno-associated viruses play an important role in understanding the structure and function of the brain [58]. They are also the star vectors in the eld of gene therapy, and can be used in the treatment of various genetic defects, such as Parkinson [59], hemophilia [60,61], and lysosomal disease [62], etc. Here, we have endowed the AAV9 capsid with e cient retrograde transduction capacity in mouse brain by inserting the 10-mer peptide sequence (LADQDYTKTA) from AAV2-Retro (AAV2 libraries) in between Q588 and A589.…”

Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes?

“…[27][28][29][30] The size of the CDS of additional large proteins has been optimized to fit into AAV vectors. [31][32][33][34] Some of these mini-protein versions have already reached the clinical stage, 35 whereas other forms of therapeutic applicability are still under preclinical investigation, to deeply evaluate retention of the proper functionality. 36 For many diseases, however, the generation of truncated versions that retain protein function has so far not been achieved.…”