Gene Therapy in Hemophilia: Recent Advances

Rodríguez-Merchán, E. Carlos; Pablo-Moreno, Juan A. De; Liras, Antonio

doi:10.3390/ijms22147647

Cited by 33 publications

(33 citation statements)

References 71 publications

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“…In our opinion, although current studies focus mainly on the clinical applications of the prophylaxis and gene therapy [ 3 , 99 , 100 ], more efforts should be devoted to uncovering the molecular mechanisms of FIX deficiency, which may lead to new strategies of precisely treating hemophilia B based on various mechanisms. For nonsense mutations, it is promising to develop new drugs to induce ribosome readthrough, which permits the secretion of full-length FIX [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis of FIX Deficiency in Hemophilia B

Shen

Gao

Cao

et al. 2022

IJMS

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Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

The Molecular Basis of FIX Deficiency in Hemophilia B

Shen

Gao

Cao

et al. 2022

IJMS

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“…The greatest strides have been taken in the field of gene therapy, where partially integrative adeno-associated viral vectors have been successfully used to treat hemophilia A and B [ 97 ]. However, no advanced-therapy approach has as yet been proposed to address other congenital coagulopathies.…”

Section: Discussionmentioning

confidence: 99%

High Mutational Heterogeneity, and New Mutations in the Human Coagulation Factor V Gene. Future Perspectives for Factor V Deficiency Using Recombinant and Advanced Therapies

Bernal

Peláez

Alías

et al. 2021

IJMS

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Factor V is an essential clotting factor that plays a key role in the blood coagulation cascade on account of its procoagulant and anticoagulant activity. Eighty percent of circulating factor V is produced in the liver and the remaining 20% originates in the α-granules of platelets. In humans, the factor V gene is about 80 kb in size; it is located on chromosome 1q24.2, and its cDNA is 6914 bp in length. Furthermore, nearly 190 mutations have been reported in the gene. Factor V deficiency is an autosomal recessive coagulation disorder associated with mutations in the factor V gene. This hereditary coagulation disorder is clinically characterized by a heterogeneous spectrum of hemorrhagic manifestations ranging from mucosal or soft-tissue bleeds to potentially fatal hemorrhages. Current treatment of this condition consists in the administration of fresh frozen plasma and platelet concentrates. This article describes the cases of two patients with severe factor V deficiency, and of their parents. A high level of mutational heterogeneity of factor V gene was identified, nonsense mutations, frameshift mutations, missense changes, synonymous sequence variants and intronic changes. These findings prompted the identification of a new mutation in the human factor V gene, designated as Jaén-1, which is capable of altering the procoagulant function of factor V. In addition, an update is provided on the prospects for the treatment of factor V deficiency on the basis of yet-to-be-developed recombinant products or advanced gene and cell therapies that could potentially correct this hereditary disorder.

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“…gene therapy) offering a potential cure, which are only available for a limited number of patients. 4 Patients require life-long expensive factor replacement therapy. Thus, the majority of PWH in developing countries are deprived of standard treatment.…”

Section: Haemophilia In South Asia: a Perspective From Bangladeshmentioning

confidence: 99%