Functionalized antibodies, protein subs titution, supplementation therapies, and enzyme-based therapeutics are protein-based approaches for the treatment and cure of human genetic and acquired diseases. Gene editing and RNA-based therapeutics, including siR NAs, microRNAs, and antisense oligonuc leotides (ASOs), target the ma- chinery that produces disease-associat ed proteins. Protein-based and RNA-based products are collectively referred to as biologics. This Thematic Issue opens a novel specialized s ection of Current Medicinal Chemistry focused on targeted biologics at various stages of discovery, preclinical and clinical development. We hope it might encourage the advancement of this field by stimulating researchers to share their results. Within this issue, readers will find papers discussing th e use of replacement proteins therapeutics, with two ex- amples provided. Alpha-1-antitrypsin and C-1 inhibitor (or C1-esterase inhibitor) both belong to the family of ser- pins and are indicated for the treatment of conditions that result from pat hologically low levels or non-functional variants. Alpha-1-antitrypsin is a small protein that inhib its the catalytic action of el astase, a proteolytic enzyme. When the action of elastase is not properly counterbalan ced by alpha-1-antitrypsin in the lung, pulmonary emphy- sema develops. Alpha-1-antitrypsin was approved more than thirty years ago and is used for the treatment of Alpha- 1-antitrypsin deficiency. The paper by Bianchera et al. [1] reports on issues associated with alpha-1-antitrypsin pro- duction from either animal sources or heterologous expre ssion, focusing on existing and novel protein formulations and delivery strategies. The C-1 inhibitor is involved in a re gulatory network of comple ment, contact, coagulation, fibrinolytic systems and functions as an anti-inflammatory agent in circulation. C-1 inhibitor is used as a prophylactic or acute treatment in Hereditary Angioedema (HAE), which is a rare genetic disease. The paper by Karnaukhova et al. [4] provides an overview of the biochemical properties of C-1 inhibitor, its role in HAE, recent progress in therapeutic strategies for this disease treatment, as well as potential applications fo r sepsis, endotoxin shock, antibody-mediated rejection fol- lowing kidney transplantation, and severe systemic abnormalities related to COVID-19. During the Vietnam War in the late 1960s, the United States started searching for blood substitutes, such as mod- ified hemoglobin or perfluorocarbon solutions, to replace transfusions when blood was unavailable. Since then, many attempts have been carried out, including the devel opment of chemically and/or genetically modified hemo- globins designed to mimic red blood cells. The paper by Sakai et al. [7] summarizes the intense activities carried out predominantly in Japan towards th e development of hemoglobi n-containing liposomes. Issues associated with lipids purity, hemoglobin purification, and stability towards oxidation are presented and discussed. There are many pathophysiologic aberrati ons associated with genetic variants of hemoglobin, often caused by single amino acid substitutions. One such example is the single amino acid Glu-Val substitution at position 6 of the beta chains, leading to sickle cell disease. Hydroxyurea is a mainstay of sickle cell disease therapy to increase the percentage of fetal hemoglobin. Novel marketed therap eutics are based on compounds either interacting directly with hemoglobin to modulate oxygen binding or altering water-controlling pump systems. Alternative and more recently proposed approaches are based on hematopoietic st em cell transplantation and gene therapy platforms. These approaches are reviewed by Garg et al. [3] which discuss advances in precision therapy for sickle cell disease and the preclinical and clinical advances in autologous hematopoietic stem cell gene therapy. Breathing is a fundamental function for all living systems. It is made possible in both animals and humans by the presence of pulmonary surfactant, a complex mixture of lipids and proteins secreted into the alveolar lumen. Its role is the maintenance of lung homeostasis to avoid alveolar collapse. In addition, pulmonary surfactant provides a bar- rier against inhaled pathogens. An insufficient amount of su rfactant or its functional inac tivation is associated with lung pathologies, including neonatal resp iratory distress syndrome. Pioselli et al. [6] reviewed the current state of pulmonary surfactant mimetics in development for replacement therapy. Presently, there are lifesaving products in this class approved for worldwide use in premature infants. Because novel proteins being studied in developmental stages are typically extracted from porcine sources, the pr oduction strategies for tailored surfactant proteins by re- combinant technologies are being refined. Further, pulmonary surfactants ar e attractive candidates for synergistic and carrier molecules that enhance the treatment of a variety of respiratory diseases. Enzymes are biomolecules that catalyze an impressive variety of chemical reactions. A key feature of an enzyme is its specificity for specific substrates. Therefore, it is not surprising that enzymes have been attractive for carrying out selective therapeutic actions. There are two main medicinal strategies based on enzymes: i) supplementation and ii) replacement. Cioni et al. [2] focused on a range of disorders wher e the supplementation of enzymes to patients provides the basis for therapeutic interventions, including clotting disorders, cystic fibrosis, lactose intolerance, col- lagen-based disorders, and cancers. Enzymes for therapeutic indications are increasing as a result of advancements in genetic engineering techniques. Typi cal examples are asparaginase and methionine gamma-lyase, used in cancer therapy to degrade either asparagine or methionine, respec tively. The rationale is based on the vital need for these amino acids by cancer cells. Depletion of these amino acids in the cellular environment slows or prevents cancer cell growth, potentiating the efficacy of traditional chemotherapies. Because enzymes are very "fragile" biomole- cules, novel strategies are being employed to optimize their stability and delivery. Enzyme replacement therapy is also the focus of the paper by Marchetti et al. [5]. Genetic deficiencies of a specific enzyme can lead to the accumu- lation of its substrates and toxic effect s. For example, Gaucher and Fabry diseases are the first rare genetic lysoso- mal storage disorders for the treatment of which enzymes were successfully delivered. In these examples, enzymes were initially obtained from animal sources, then produced using recombinant technology with chemical modifica- tions or genetic variants to enhance and extend their activity. This first issue of the Targeted Biologics represents a small sampling of successful applications of biologics. We are confident that Current Medicinal Chemistry readers will find these examples intellectually stimulating and allow the journal to advance exciting concepts in Biologics for targeted therapy.

Targeted Biologics: The New Frontier for Precision Therapy

Mozzarelli Andrea;
2022

Abstract

Functionalized antibodies, protein subs titution, supplementation therapies, and enzyme-based therapeutics are protein-based approaches for the treatment and cure of human genetic and acquired diseases. Gene editing and RNA-based therapeutics, including siR NAs, microRNAs, and antisense oligonuc leotides (ASOs), target the ma- chinery that produces disease-associat ed proteins. Protein-based and RNA-based products are collectively referred to as biologics. This Thematic Issue opens a novel specialized s ection of Current Medicinal Chemistry focused on targeted biologics at various stages of discovery, preclinical and clinical development. We hope it might encourage the advancement of this field by stimulating researchers to share their results. Within this issue, readers will find papers discussing th e use of replacement proteins therapeutics, with two ex- amples provided. Alpha-1-antitrypsin and C-1 inhibitor (or C1-esterase inhibitor) both belong to the family of ser- pins and are indicated for the treatment of conditions that result from pat hologically low levels or non-functional variants. Alpha-1-antitrypsin is a small protein that inhib its the catalytic action of el astase, a proteolytic enzyme. When the action of elastase is not properly counterbalan ced by alpha-1-antitrypsin in the lung, pulmonary emphy- sema develops. Alpha-1-antitrypsin was approved more than thirty years ago and is used for the treatment of Alpha- 1-antitrypsin deficiency. The paper by Bianchera et al. [1] reports on issues associated with alpha-1-antitrypsin pro- duction from either animal sources or heterologous expre ssion, focusing on existing and novel protein formulations and delivery strategies. The C-1 inhibitor is involved in a re gulatory network of comple ment, contact, coagulation, fibrinolytic systems and functions as an anti-inflammatory agent in circulation. C-1 inhibitor is used as a prophylactic or acute treatment in Hereditary Angioedema (HAE), which is a rare genetic disease. The paper by Karnaukhova et al. [4] provides an overview of the biochemical properties of C-1 inhibitor, its role in HAE, recent progress in therapeutic strategies for this disease treatment, as well as potential applications fo r sepsis, endotoxin shock, antibody-mediated rejection fol- lowing kidney transplantation, and severe systemic abnormalities related to COVID-19. During the Vietnam War in the late 1960s, the United States started searching for blood substitutes, such as mod- ified hemoglobin or perfluorocarbon solutions, to replace transfusions when blood was unavailable. Since then, many attempts have been carried out, including the devel opment of chemically and/or genetically modified hemo- globins designed to mimic red blood cells. The paper by Sakai et al. [7] summarizes the intense activities carried out predominantly in Japan towards th e development of hemoglobi n-containing liposomes. Issues associated with lipids purity, hemoglobin purification, and stability towards oxidation are presented and discussed. There are many pathophysiologic aberrati ons associated with genetic variants of hemoglobin, often caused by single amino acid substitutions. One such example is the single amino acid Glu-Val substitution at position 6 of the beta chains, leading to sickle cell disease. Hydroxyurea is a mainstay of sickle cell disease therapy to increase the percentage of fetal hemoglobin. Novel marketed therap eutics are based on compounds either interacting directly with hemoglobin to modulate oxygen binding or altering water-controlling pump systems. Alternative and more recently proposed approaches are based on hematopoietic st em cell transplantation and gene therapy platforms. These approaches are reviewed by Garg et al. [3] which discuss advances in precision therapy for sickle cell disease and the preclinical and clinical advances in autologous hematopoietic stem cell gene therapy. Breathing is a fundamental function for all living systems. It is made possible in both animals and humans by the presence of pulmonary surfactant, a complex mixture of lipids and proteins secreted into the alveolar lumen. Its role is the maintenance of lung homeostasis to avoid alveolar collapse. In addition, pulmonary surfactant provides a bar- rier against inhaled pathogens. An insufficient amount of su rfactant or its functional inac tivation is associated with lung pathologies, including neonatal resp iratory distress syndrome. Pioselli et al. [6] reviewed the current state of pulmonary surfactant mimetics in development for replacement therapy. Presently, there are lifesaving products in this class approved for worldwide use in premature infants. Because novel proteins being studied in developmental stages are typically extracted from porcine sources, the pr oduction strategies for tailored surfactant proteins by re- combinant technologies are being refined. Further, pulmonary surfactants ar e attractive candidates for synergistic and carrier molecules that enhance the treatment of a variety of respiratory diseases. Enzymes are biomolecules that catalyze an impressive variety of chemical reactions. A key feature of an enzyme is its specificity for specific substrates. Therefore, it is not surprising that enzymes have been attractive for carrying out selective therapeutic actions. There are two main medicinal strategies based on enzymes: i) supplementation and ii) replacement. Cioni et al. [2] focused on a range of disorders wher e the supplementation of enzymes to patients provides the basis for therapeutic interventions, including clotting disorders, cystic fibrosis, lactose intolerance, col- lagen-based disorders, and cancers. Enzymes for therapeutic indications are increasing as a result of advancements in genetic engineering techniques. Typi cal examples are asparaginase and methionine gamma-lyase, used in cancer therapy to degrade either asparagine or methionine, respec tively. The rationale is based on the vital need for these amino acids by cancer cells. Depletion of these amino acids in the cellular environment slows or prevents cancer cell growth, potentiating the efficacy of traditional chemotherapies. Because enzymes are very "fragile" biomole- cules, novel strategies are being employed to optimize their stability and delivery. Enzyme replacement therapy is also the focus of the paper by Marchetti et al. [5]. Genetic deficiencies of a specific enzyme can lead to the accumu- lation of its substrates and toxic effect s. For example, Gaucher and Fabry diseases are the first rare genetic lysoso- mal storage disorders for the treatment of which enzymes were successfully delivered. In these examples, enzymes were initially obtained from animal sources, then produced using recombinant technology with chemical modifica- tions or genetic variants to enhance and extend their activity. This first issue of the Targeted Biologics represents a small sampling of successful applications of biologics. We are confident that Current Medicinal Chemistry readers will find these examples intellectually stimulating and allow the journal to advance exciting concepts in Biologics for targeted therapy.
2022
Istituto di Biofisica - IBF
Targeted Biologics: The New Frontier for Precision Therapy
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/448251
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 2
social impact