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α1-Antitrypsin deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The relationship of protease and elastin has led to understanding of the pathogenesis of emphysema not only in this common disease, but in other nongenetic forms of emphysema. The gene has been isolated. Recombinant techniques have made abundant supplies of α1-AT for protein replacement therapy [15, 16], and gene replacement has been done in transgenic animals [17, 18]. In addition, the relationship between cigarette smoking and the occurrence of emphysema in individuals that have inherited this susceptibility [19] provides an interesting example of the interaction of genetics and environment, and the development of emphysema in non-α1-AT deficient smokers has provided a strong scientific argument against smoking [20].
Epidermolysis bullosa
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Understanding the molecular basis of EB has led to the development of novel genetic and cellular therapies. Hematopoietic cell transplantation, gene therapy, protein replacement therapy, and cell-based therapies have been researched for the treatment of EB [17]. Gene and cell therapies hold great promise, especially for recessive forms of EB. The first skin gene therapy trial was done in JEB. Intradermal injection of allogeneic fibroblasts temporarily stimulates increased expression of type VII collagen in patient fibroblasts in the less severe form of RDEB. Mesenchymal stem cell transplant has been shown to produce collagen VII to the basement membrane and improvement in RDEB [17].
Genome Editing for Genetic Lung Diseases
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Although it is attractive to transform the precise genome editing therapy into clinics, the therapeutic genome editing for lung diseases faces strong competitions from small molecule drugs, protein replacement therapy, and RNA inference therapy. It is likely that the next generation of CFTR protein correctors, presented as small molecules, would benefit more than 90% of cystic fibrosis patients carrying one or both copies of delta508 mutations, leaving 6%–8% patients without effective treatment.155 Infusion of AAT protein, gene transfer of AAT, or a potential AAT protein corrector might treat all AAT disorders.31,97,156,157 Although small interfering RNAs did not obtain statistically significant outcome in a phase II trial for treating respiratory syncytial virus (RSV) infection, a more potent and stable form of siRNA has been developed.158,159 Nevertheless, a successful genome editing program may make use of undruggable targets and/or provide a better therapeutic outcome.
Molecular therapeutics of hemophilia A and B
Published in Expert Review of Hematology, 2022
Jie Gong, Hao-Lin Wang, Lung-Ji Chang
The current treatment for HA is based on protein replacement therapy (PRT) through plasma-derived coagulation factors or recombinant proteins produced in culture. HA patients who receive prophylactic treatment would experience reduced joint bleeding episodes and other hemorrhages [11]. The limitations of PRT include the formation of neutralizing anti-FVIII antibodies (inhibitors), short half-life, high cost of recombinant concentrations, the frequent intravenous administration, and lifetime requirements of the treatment. Frequent intravenous administration is responsible for a loss of adherence to prophylaxis treatment. All of the new non-replacement molecules (emicizumab, concizumab, and fitusiran) are administered subcutaneously. Unlike the success with long-acting factor IX, producing very long half-life FVIII has been difficult. Much effort has been made including chemical modification (PEG and sialylation), protein fusion (Fc, XTEN, or albumin), and sequence modification. With these modifications, the frequency of infusion can be reduced. Nevertheless, the inhibitor formation remains to be a challenge affecting many HA patients.
Non-neutralizing antibodies increase endogenous circulating Ang1 levels
Published in mAbs, 2018
Chao Zheng, Joshuaine Toth, Tammy Bigwarfe, Margit MacDougall, Kavita Jerath, Kristin Bovat, James Smith, Peng Sun, David Hayes, Ryan Fryer, Sanjaya Singh, Rachel Kroe-Barrett
Monoclonal antibodies (mAbs) are proving to be successful therapeutic agents, owing to their high degree of specificity, favorable pharmacokinetic (PK) and safety profiles, well-established manufacturing processes, and advantageous biophysical properties. Their therapeutic effects against soluble proteins are usually achieved by blocking ligand-receptor interactions with neutralizing antibodies.1 However, there may be cases in which therapeutic outcomes are achieved by increasing a circulating protein level. Although protein replacement therapy or gene therapy may be considered to boost the circulating level of a soluble protein, there are drawbacks to these procedures, such as poor manufacturability or safety risks.
The availability of new drugs for hemophilia treatment
Published in Expert Review of Clinical Pharmacology, 2020
Massimo Morfini, Emanuela Marchesini
Concizumab is a monoclonal, humanized IgG4 antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit hemophilia model. Restoration of thrombin generation is increasingly considered as a therapeutic intervention to overcome the limitations of protein replacement therapy. Anti-TFPI monoclonal antibodies restore thrombin generation by abolishing the inhibitory effect of TFPI on the initiation of coagulation.