Future Of COPD Treatment Short.pptx

COPD New Treatment, Future

1. Future Trends In COPD Management Prof. Waheed Shouman Chest Medicine Department Zagazig University

2. COPD:

3. Global Causes of Death (WHO 2019-2020) (White 2020 , blue 2019 )

4. The 5-year life expectancy for people with COPD ranges from 40% to 70%, depending on disease severity. For men aged 65 who smoke, the drop in life expectancy is: • Stage 1: 0.3 years • Stage 2: 2.2 years • Stage 3: 5.8 years • Stage 4: 5.8 years This is in addition to the 3.5 years of life all smokers, whether they have COPD or not, lose to the habit.

5. Milestones in Current Management of COPD

6. GOLD 2001 for COPD management (1 st )

7. GOLD 2023 for COPD management (Last)

8. Treatment of COPD benefit from the use of fixed dose combinations of two or more drug classes. Treatment of COPD is dominated by inhaled fixed dose combination. Formulations to allow the use of more than one drug in a single inhaler is problematic There are differences in duration of action of the mono-components and issues concerning chemical compatibility and stability as well the different physiochemical properties of the different drug classes.

9. New LABAs: Abediterol is a novel and selective long acting B2-agonist with the potential for once daily treatment of COPD. It has superior bronchodilatory efficacy, and superior selectivity for B2-receptors over current LABAs (formoterol and indacaterol). The duration of abediterol is similar or superior to other LABA compounds, with a reduced effect on heart rate.

10. Bifunctional Bronchodilator Drugs: An alternative approach to delivering complementary pharmacological activities is to develop molecules having two distinct primary pharmacological actions. MABAs, is one of these, which have both β2-agonist activity and muscarinic receptor antagonism in the same molecule. It is not clear the relative contribution of the two different pharmacological activities to the overall improvement in lung function.

11. Bifunctional Bronchodilator Drugs: Examples: GSK 961081 ( batefenterol ) THR 200495 is comparable to a combination of salmeterol and tiotropium. AZD 2115 LAS 190792 TEI3252 PF-3429281 PF-4348235

12. Bifunctional Bronchodilator Drugs: Clinical study showed that treatment with batefenterol is superior in improvements of lung function in patients with COPD compared with salmeterol MABA provides a better treatment than monotherapy with a β2-agonist.

13. Non-steroidal, Selective Glucocorticoid R eceptor Modulator (SGRM): They dissociate the anti-inflammatory effects from the adverse effects induced by corticosteroids Valsecorat 200 μ g, 400 μ g, and 1600 μ g via pMDI are under trial for safety and efficacy. Valsecorat is a once-daily drug.

14. New Macrolides: Treatment with the novel macrolide oral Solithromycin at 400 mg did not significantly improve FEV1 compared to placebo. No SAEs were reported in the study.

15. Phosphodiasterase Inhibitors: Withdrawal of theophylline from patients with asthma or COPD leads to worsening of airways inflammation and symptoms, even in patients taking glucocorticoids and other classes of bronchodilator drug. Xanthines possess other useful pharmacological properties not shared with glucocorticoids and other classes of bronchodilator. The problem with xanthines is the narrow safety profile.

16. Phosphodiasterase Inhibitors: Pharmaceutical companies tried to find safer xanthines A number of them has been investigated: Enprophylline (1985) Bamiphylline (1991) Isbuphylline ( 1993) Doxophylline (2010) which have been approved for the treatment of asthma and COPD Acebrophylline ( 2014)

17. Phosphodiasterase Inhibitors: Another approach to try and improve the therapeutic window of xanthines is to develop more selective inhibitors of the family of PDEs. PDEs, with 11 families (PDE1-PDE11) are a superfamily of enzymes that specifically hydrolyze the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Functional disorders of PDE4, PDE7, and PDE8 are associated with developing multiple neurological and cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and brain tumorigenesis.

18. Phosphodiasterase Inhibitors: PDE 3 and 4 are found in airway smooth muscle. PDE 3, 4 and 7 are found in the majority of inflammatory cellsad are involved in the pathogenesis of COPD. PDE3 isoenzyme is in airway smooth muscle, and inhibition of this enzymeleads to airway smooth muscle relaxation. PDE4 isoenzyme is the predominant isoenzyme in most inflammatory cells, including neutrophils, which are implicated in the pathogenesis of COPD. The nausea and vomiting side effects of PDE4 inhibitors have greatly limited their clinical usefulness.

19. Phosphodiasterase Inhibitors: PDE-3 Inhibitors: PDE-3 inhibitors have been shown to cause acute bronchodilation in humans. The first drug was Zardaverine , which showed bronchodilation in patients with asthma but unfortunately was halted during clinical development because of gastrointestinal side effects. Benzafentrine , which caused bronchodilation but was later discontinued from clinical development, due to GIT upset Dual PDE 3/4 inhibitor, Pumafentrine was discontinued due to GIT side effects.

20. Phosphodiasterase Inhibitors: PDE-4 Inhibitors: Four PDE4 inhibitors have been approved for the treatment of human diseases. Roflumilast for COPD in 2010 and plaque psoriasis by 2022. Apremilast for psoriatic arthritis in 2014. Crisaborole for atopic dermatitis in 2016. Ibudilast for the rare child disease Krabbe in 2016 and for bronchial asthma in1989. The side effect profile of this drug still limits the wider use of this agent. The clinical benefit of Roflumilast is due to the anti-inflammatory action of this selective PDE4 inhibitor.

21. Phosphodiasterase Inhibitors: PDE-4 Inhibitors: To improve the therapeutic window of PDE4 inhibitors, several inhaled drugs have been developed PDE4 inhibitor. These drugs have shown little or no efficacy in patients with COPD. The exception is CHF6001 which inhaled on top of standard of care for 32 days was well tolerated and reduced multiple biomarkers of airway inflammation in induced sputum, and serum surfactant protein D in patients with COPD and chronic bronchitis. CHF6001 is currently in clinical trials for COPD.

22. PDE-4 inhibitors ( Up to 57 compounds are approved or under trial in 2023 )

23. PDE-4 inhibitors

24. PDE-4 inhibitors

25. Phosphodiasterase Inhibitors: PDE-3/4 Inhibitors: In short-term studies, Ensifentrine significantly reduced lung volumes and airway resistance. In a four-week study, 4 Ensifentrine significantly improved bronchodilation and symptoms, and was well tolerated in patients with COPD. Ensifentrine has entered Phase III clinical development. Ensifentrine administered at 6 mg via jet nebulizer was as effective as ipratropium 40 μ g and salbutamol 200 μ g via pressurized MDI ( pMDI )

26. Phosphodiasterase Inhibitors: PDE-5 Inhibitors: PDE5 inhibitors such as sildenafil can induce bronchodilation in addition to their well-documented effects on pulmonary vascular smooth muscle and suppress the pulmonary inflammation and airway hyperreactivity . It has been suggested that a new molecule that inhibits both PDE4 and PDE5 could act at multiple levels in patients with COPD leading to: Reduced lung inflammation Reduced remodelling Decreased arterial pulmonary hypertension Improved lung function

27. Phosphodiasterase Inhibitors: PDE-5 Inhibitors: One such example is LASSBio596, is a hybrid of thalidomide and aryl sulfonamide It has a potent inhibitory effects on both PDE4 and PDE5. In a murine model of elastase-induced emphysema, LASSBio596 reduced lung inflammation and remodelling and improved lung mechanics It has been documented that LASSBio596 has the potential to block proliferation of fibroblasts.

28. Phosphodiasterase Inhibitors: PDE-7 Inhibitors: The PDE7 family was first reported in 1993. The inhibition of PDE7 maybe not cause emetic-like effects. The inhibition of PDE7 alone unaffected proinflammatory cells but enhanced the effects of other cAMP-elevating drugs (such as PDE4 inhibitors). Several compounds that exhibit dual inhibition of PDE3/PDE4 or PDE4/PDE7 have been reported

29. Phosphodiasterase Inhibitors: PDE-7 Inhibitors: Types of PDE-7 inhibitors: Pyrimidinones-based PDE7 inhibitors. One of them: Spiro-quinazolinone analogues. The first Quinazolinone-based PDE7 inhibitor was spiro-quinazolinone 26. Pyridine and pyridinone analogues as PDE7 inhibitors Pyrimidine-based PDE7 inhibitors Benzenesulfonamide -based PDE7 inhibitors Other heterocyclic derivatives as PDE7 inhibitors

30. Phosphodiasterase Inhibitors With Bronchodilator: GS-5759 is a bifunctional PDE4 inhibitor/LABA drug that displays PDE4 inhibition and β2 agonism comparable to roflumilast and indacaterol. Bifunctional compounds containing a PDE4 inhibitor connected to a antimuscarinic have been described.

31. Inhaled Heparin in COPD : Heparins have anti-inflammatory, antioxidant, mucoregulatory , mucolytic, and tissue repair properties. All studies reported improvements in pulmonary function irrespective of administration via the subcutaneous, intravenous, or inhaled route, with no effects on systemic coagulation parameters. COPD patients received nebulised inhaled UFH ( 75,000 or 150,000 IU twice a day) or placebo for 21 days. All patients also received nebulised salbutamol and beclomethasone twice daily over the same period. UFH significantly increased FVC following 7 days of treatment with both doses. The higher dose, 150,000 IU b.i.d., significantly increased FEV1 (+249 ± 69 mL compared with placebo) following 7 days of treatment. With both doses of UFH, a clinically significant improvement.

32. L-Menthol : L-Menthol is effective in relieving breathlessness in patients with COPD. Augmented inspiratory flow perception by L-menthol is important in relieving breathlessness. The application of L-menthol to inspiratory muscle training and exercise is to be expected. L-Menthol did not affect the inspiratory neural drive or breathing patterns. L-Menthol induced a ‘cognitive illusion’ of inspiratory flow by stimulating nasal afferent receptors involved in the detection of cooling sensations, and that this led to a rationalization associated with a favourable reduction in breathlessness.

33. Mitochondria-Targeted Antioxidants in COPD

34. Inhaled A1-AntiTrypsin Replacement T herapy : AAT is given twice weekly intravenously. Only 2–3% of intravenous AAT reaches the lung. Weekly intravenous administration of 60-120 mg/kg of AAT is under trial Inhaled AAT to may help by acting directly on the organ of interest. However, these come with limitations, including the delivery of AAT to the alveoli via nebulizers can take up to 100 min, and may be less effective in patients with low FEV1 and the amount of AAT needed in the interstitium to prevent disease is unclear.

35. Inhaled A1-AntiTrypsin Replacement T herapy : Higher local AAT levels in the airway epithelial lining fluid have been achieved with the inhaled route compared to delivery with the intravenous route. In AAT deficiency patients with severe COPD and frequent AECOPDs, AAT inhalation had no effect on the time to first AECOPD during treatment for 50 weeks. Inhaled “ Kamada -AAT” is a promising drug, with plasma-derived high purity solution for inhalation.

36. Selectin Antagonists: Selectins are essential for migration of inflammatory cells from the bloodstream into pulmonary tissue They mediate transient adhesive interactions related to inflammation. There are three members of the selectin family ( E-, L-, P selectin). E- and P-selectin are expressed on endothelium, whilst L-selectin is expressed on leukocytes.

37. Selectin Antagonists: Inhaled Bimosiamose is a synthetic pan-selectin antagonist that has shown encouraging results in a phase IIa trial in patients with COPD. After its administration for 4 weeks, it induced an attenuation of airway inflammation and small lung function improvements. Uproleselan , a specific inhibitor of E-selectin, and Rivipansel (GMI-1070), a pan-selectin antagonist, have been tested in humans, but not yet in patients with COPD.

38. CXCR1 and CXCR2 Antagonists: Neutrophils have the chemokine receptors CXCR1 and CXCR2, of which CXCR2 is more responsible for chemotaxis and adhesion. Several CXCR2 antagonists, such as SCH5 27123, SB-656933, QBM076, AZD5069 and Navarixin , have been investigated as potential treatments for COPD, but the Phase II studies had to be terminated due to adverse events. MK-7123 (also known as SCH 527123) is a chemokine receptor antagonist with high affinity of CXCR2. MK-7123 50 mg led to a significant improvement in FEV1. There was reduced sputum neutrophil count at 3 and 6 months. However, MK-7123 caused a dose-dependent decrease in absolute neutrophil.

39. Interleukin-8/CXCR2 Several CXC-chemokines, of which interleukin (IL)-8 is the prototype, are potent neutrophil chemotactic and activating cytokine IL-8 is a potent chemoattractant for neutrophils and a member of the CXC family of chemokines . It has been evaluated as a possible target for biologic therapy. A monoclonal IgG2 antibody against human IL-8 (ABX-IL8) has been developed and studied in COPD patients. Final results showed a reduced severity of dyspnea in those treated with ABX-IL8, but the difference was only significant at 2 weeks.

40. CXCR1 and CXCR2 Antagonists: Danirixin has been evaluated in 52-week RCT in stable COPD patients. It significantly improved symptoms (breathlessness, cough and sputum) and also decreased the number of days free from AECOPDs compared with placebo. However, in a 24-week, Phase II study that enrolled over 600 COPD patients, Danirixin did not significantly improve AECOPD or change respiratory symptoms. Also, a 26-week Phase IIb RCT in patients with COPD at risk for AECOPDs failed to show any benefit on the incidence and severity of respiratory symptoms but reported a high incidence of AECOPDs and incidence of pneumonia. There was no significant difference in FEV1 between Danirixin administered orally at 75 mg and placebo.

41. IL-17 Antagonists: IL-17 is secreted from T helper 17 (Th17) cells and mediates neutrophilic inflammation by increasing release of CXCL8 (IL-8) from airway epithelial cells. IL-17 in COPD is increased in bronchial biopsy samples and lung and sputum of patients of COPD. Several anti–IL-17 monoclonal antibodies have been developed, including Ixekizumab , Brodalumab , and Secukinumab , for psoriasis . Secukinumab did not attenuate acute ozone-induced airway neutrophilia in healthy subjects. CNTO 6785 did not demonstrate in patients with COPD. Furthermore, an increased rate of AECOPDs was observed. Brodalumab did not result in a significant effect in patients with controlled asthma.

42. Neutrophil Elastase I nhibitors : NE is the primary enzyme present in azurophil granules in the neutrophil cytoplasm. Sivelestat is on the market in Japan and South Korea for the treatment of ARDS. There are several NE inhibitors in various stages of development but are not focused on COPD. Alvelestat is currently in clinical trials in patients with a1-antitrypsin (AAT) deficiency. It did not show clinical benefit and effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD.

43. Eosinophilic Inflammation in COPD: Eosinophilic inflammation has been reported in 20% to 40% of induced sputum in patients with stable COPD. Eosinophilic inflammation increases in exacerbations. Bronchial biopsies done during acute exacerbations compared with stable COPD had a 30-fold increase in total number of eosinophils. Blood eosinophilia isassociated with increased mortality in COPD exacerbations. Several cytokines are involved in eosinophilic inflammation, including IL-5, IL-4, and IL-13.

44. Eosinophilic Inflammation in COPD: Benralizumab is a monoclonal antibody that targets the human IL-5 receptor alpha. Benralizumab was evaluated in patients with COPD with sputum eosinophil counts of 3% or more. Benralizumab did not reduce the rate of COPD exacerbations. However, there were improvement in FEV1.

45. Eosinophilic Inflammation in COPD: The data on the role of IL-13 and IL-4 are conflicting in COPD. The main evidence for IL-4/IL-13 in COPD is based on a mouse model of COPD. Dupilumab, lebrikizumab, and tralokinumab have not been extensively studied in COPD. Targeting IL-4 and IL-13 may prove beneficial in a subgroup of Th2-high patients with COPD, in patients with Asthma/COPD Overlap Syndrome (ACOS), and/or in COPD exacerbations.

46. Eosinophilic Inflammation in COPD: As of early 2018, no anti–IL-5 therapies was studied in COPD 2 Mepolizumab phase studies showed improvements in exacerbation frequency in subjects treated with Mepolizumab who had an eosinophilic phenotype and a history of COPD exacerbations, despite triple therapy. Patients treated with Mepolizumab 100 mg once monthly had a significantly lower annual exacerbations compared with subjects treated with placebo.

47. Matrix MetalloPeroxidase Inhibitors: The development of drugs inhibiting MMPs is still at an early stage. V85546, a selective MMP-12 inhibitor, and AZD1236, a MMP-9 and MMP-12 inhibitor have been tested in humans. V85546 completed phase I clinical testing, whereas AZD1236 showed no clinical efficacy in the short term after 6-weeks treatment in patients with COPD

48. Phosphoinositide 3-kinase (PI3K) inhibitors: PI3K is important in the activation of macrophage and neutrophils. PI3K function may be altered in COPD. In healthy smokers, Nemiralisib , a potent inhaled PI3Kd inhibitor that is > 1000-fold more selective at PI3Kd, showed acceptable tolerability with significantly higher levels of the drug in the lung compared with plasma.

49. p38 MAPK inhibitors: Mitogen-activated protein kinases (MAPKs) play a key role in chronic inflammation. Inhaled p38 MAPK inhibitors may enhance p38 inhibition in the lung while reducing unwanted systemic effects. The p38 MAPK inhibitors PF-03715455, losmapimod (GW856553) and AZD7624 are tested. The effect of PF-03715455 administered at 680 μg via inhalation was not effective in improving FEV1. Oral Losmapimod 15 mg did not change FEV1, SGRQ, and risk of COPD exacerbation. AZD7624, a dual p38a/b inhibitor, had a greater effect than budesonide on cytokine production from bronchial epithelial cells in COPD patients, but failed to provide any benefit in a 3-month AECOPD Phase IIa RCT.

50. Janus-kinase Inhibitors: Janus-kinases (JAKs)-signal transducers and activators of transcription (STATs) signalling pathways may be involved in the pathogenesis of COPD. A pan-JAK inhibitor (PF-06263276) suitable for inhaled administration in COPD patients has passed the preclinical phase. It showed a dose-related inhibition of IL-6-induced increases of pSTAT3 in murine lung . Pyridone 34 is an inhaled potent pan-JAK inhibitor with a dose-dependent inhibition of BAL neutrophils and IL-6. No clinical trials have been started

51. Vasoactive Intestinal Peptides (VIP): RO 50-24118, a stable analogue of VIP It is highly selective for the VPAC2 receptor It has dual bronchodilatory and anti-inflammatory effects It relaxes airway smooth muscle cell It inhibits bronchoconstriction It attenuates the influx of neutrophils and CD8+ T cells to the inflamed lung. It may have a bronchodilator and anti-inflammatory role in COPD.

52. Club Cell Secretory Protein (CCSP) : Circulating CCSP is a strong biomarker of lung function. CCSP deficits are associated with indices of airflow limitation, Replacement therapy with CCSP has proven effective in animal models of various lung diseases, including BO , ARDS, and lung inflammation. In animal models, it did not significantly improve clinical outcomes such as oxygen usage or ventilator days.

53. Ghrelin : Ghrelin is a peptide hormone derived from ghrelinergic cells, was discovered in 1996, which is reported to be closely associated with appetite. Ghrelin is involved in various cellular events, including energy homeostasis, cholinergic–dopaminergic reward link, and endothelial function and immunomodulation. Ghrelin could inhibit the COPD-associated inflammation and autophagy. Ghrelin as therapeutic candidates targeting COPD treatment is moving from bench to clinic.

54. Autoantibodies in COPD : Autoantibodies make a significant contribution to COPD in some patients. The serum levels of autoantibodies against alveolar type II cells was elevated in human COPD patients compared with healthy control subjects. This suggests that anti-autoantibody disease therapies may be useful in patients with elevated levels of autoantibodies.

55. Gene Therapy for COPD : Gene therapy is one of the most promising strategies for the treatment of chronic lung diseases such as COPD that is progressive in nature. The first step in the treatment of COPD involves identification of the defective gene. Once it is identified, the next step would be the vector design and delivery. Adenoviral vector-based gene therapy has been regarded as best strategy for lung diseases. Viral liposome complexes carrying the AAT (α1 anti-trypsin) gene in mice produced detectable levels of AAT in the serum for up to 30 days on intravenous administration.

56. Cystic Fibrosis Transmembrane Conductance R egulator (CFTR) Modulators: CFTR modulators have the potential to be useful in COPD because dysfunction of CFTR induced by smoking-related oxidative stress. Two CFTR potentiators, Ivacaftor and Icenticaftor , were evaluated in patients with COPD. Ivacaftor did not improve FEV1, but improved symptoms, and caused a 20% improvement in CFTR activity, with no real safety concerns. Icenticaftor produced small improvement over placebo in FEV1. It also improved inflammatory markers (fibrinogen), and decreased sputum colonization.

57. New Anti- Fibrotics in COPD : Few studies addressed the role of small airway fibrosis in COPD. Signals that activate fibroblasts may include miRNAs released in extracellular vesicles from airway epithelial cells that are taken up by local fibroblasts promoting cellular senescence. Inhaled delivery of antagomirs of these mirNas to the small airways and peripheral lung of COPD patients may be effective clinically.

58. Transient Receptor Potential Channels (TRP) Transient receptor potential channels are a superfamily of 28 transmembrane cation permeable channels It is subdivided into seven families – on the basis of sequence homology Ankyrin (TRPA) Canonical (TRPC) Melastatin (TRPM) Mucolipin (TRPML) NOMPC (TRPN) Polycystin (TRPP) Vanilloid (TRPV) TRP channels have been heavily implicated with roles in COPD, namely, TRPA1, TRPV1, TRPV4 and TRPM8.

59. Transient Receptor Potential Channels (TRP) TRPV1 is well known as the receptor responsible for the perception of heat, particularly so for mediating the ‘spicy hot’ effects of capsaicin, the active constituent of chilli peppers which activates TRPV1 n sensory nerves (Role in cough) TRPV1- expressing C- fibers have been demonstrated to release pro-inflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) which mediate neurogenic inflammation (Role in inflammation) Of all the TRP channels, antagonists for TRPV1 are the most advanced in terms of drug development and clinical trials.

60. Transient Receptor Potential Channels (TRP) The main difficulties with TRPV1 antagonist development is dueto its function as a thermosensor for hot temperatures. Its adverse effects such as increased body temperature and latent withdrawal to noxious hot stimuli have dogged development. The TRPV1 antagonist AMG 517 caused significant and long-lasting increases in body temperature to above 40C. MK-2295 (or NGD-8243), caused an increase in body temperature and altering noxious heat sensation threshold.

61. Transient Receptor Potential Channels (TRP) The compound PHE377 was ‘well tolerated’, has ‘on-target activity’ and ‘does not increase body temperature’. The GSK SB-705498 for chronic refractory cough and was reported to be well tolerated, with no significant increases in tympanic temperature. This was the first TRPV1 antagonist to be examined clinically as an antitussive, but disappointingly, SB-705498 lacked efficacy in improving 24 h cough counts. XEN-D0501 was approximately 1,000 times more potent than SB-705498 at inhibiting capsaicin depolarization of human in vitro, and 100 times more potent at inhibiting capsaicin-evoked cough in conscious guinea.

62. Trials of targeting microbiome in COPD:

63. Extracellular V esicles (EVs) in COPD: Extracellular vesicles (EVs) are a general term for nanoscale lipid bilayer vesicles released upon activation, injury or apoptosis of almost all kinds of cells. Based on particle diameter size, EVs can be classified into three categories, namely exosomes (~ 40–100 nm in diameter), microvesicles (~100–1000 nm in diameter) and apoptotic vesicles (~1000–5000 nm in diameter). Research on COPD suggest that EVs have the potential to be a new therapeutic direction. There are two general approaches to treatment through EVs: (1) removal of EVs containing nucleic acids or proteins involved in disease pathogenesis, (2) use of EVs as a source of pulmonary immunomodulator.

64. Inhaled Anti-Viral Agents in COPD : Respiratory viruses together with opportunistic bacterial infections are the major causes of COPD exacerbations. Antiviral agents must be given at the earliest possible time after the viral infection to reduce the severity or prevent COPD exacerbations. Ribavirin is effective against respiratory viruses associated with COPD exacerbations including human rhinovirus ( HrV ), respiratory syncytial virus (RSV), and influenza virus. Ribavirin (cci15106, GlaxoSmithKline) by inhalation has been investigated in 2 clinical trials. It was well tolerated in healthy subjects and moderate COPD patients

65. Targeted Lung Denervation (TLD) : Bronchoconstriction and airway inflammation are mediated by the parasympathetic airway nerve fibres. TLD aims to disrupt the peri-bronchial vagal lung innervation via radiofrequency ablation under fluoroscopic guidance. It is suitable for symptomatic patients with advanced COPD (FEV1 30–60%. TLD caused reduction in COPD respiratory adverse events, in particular severe COPD exacerbations, over a year. The main concern would be the development of increased gastrointestinal events due to damage to the vagal esophageal plexus in the process of conducting TLD.

66. Senotherapy in COPD ( Senolytics )

67. Senotherapy in COPD ( Senolytics )

68. Senotherapy in COPD ( Senolytics )

69. Senotherapy in COPD ( Senolytics )

70. Drugs Stimulating L ung Regeneration: Many potential stem cell therapies already exist, but most of them are at the preclinical stages. A new potential approach to regenerative medicine is laser therapy. Lasers typically generate electromagnetic radiation which is relatively uniform in wavelength, phase and polarisation. Low Level Lasers (LLL) induce their effects through non-thermal means and may activate endogenous pulmonary stem cells and neoangiogenesis , which is optimal for stem cell growth. LLLs been proposed as regenerative photoceutical treatment for COPD. This is called Photobiomodulation (PBM). An in vivo study showed that both lasers could modulate VEGF secretion and MMP-2 activity in a dose-dependent manner.

71. Drugs Stimulating L ung Regeneration: In animal models of COPD intravenous, intratracheal and endobronchial injections of MSCs significantly attenuated emphysematous changes and significantly improved lung function. Studies have demonstrated that MSC-derived EVs, such as bone marrow, cord blood, and adipose-derived MSCs, may have a protective effect on COPD etiology.

72. Regenerative Therapies in COPD : Therapeutic attempts to stimulate lung regeneration in COPD are limited to 4 relatively short-term clinical trials with retinoids. Retioic Acid was well tolerated but no differences were observed in CT, lung function, or quality of life scores between treatment groups. Serum level decreased rapidly attributed to auto- induced catabolism, so it is unclear whether RA reached cell types necessary for repair. The findings that an RAR-γ agonist may reduce the rate of decline in a subset of patients, particularly during exacerbations, may warrant further investigation.

73. Morphologic treatments of emphysema Bullectomy Lung volume reduction surgery Bronchoscopic lung volume reduction (BLVR) Foam sealant Thermal vapor ablation Airway bypass stents Self-activating coils Endobronchial valves (EBV) Lung transplantation

74. Morphologic Treatments of COPD Airway B ypass Stents (Expandable silicone coated, paclitaxel eluting stents are placed endobronchially from emphysematous tissue into airways to promote emptying of trapped air and hence achieve reduction in lung volumes)

75. Morphologic Treatments of COPD Self-activating coils ( PneumoRx coils) They are self-activating nitinol coils that work by compressing lung parenchyma once they are deployed leading to volume reduction with atelectasis.

76. Morphologic Treatments of COPD Airway predominant treatments (No specific medical intervention has been shown to alleviate chronic bronchitis in any clinically meaningful way. New interventions have been proposed to address this clinical void by using either metered dose nitrogen cryospray or rheoplasty to eliminate airway epithelium goblet cell hyperplasia and reduced mucous hypersecretio )

77. Morphologic Treatments of COPD Lun g Sealants : Application of biological adhesives within the targeted airways to deactivate surfactant and promote local atelectasis, induce local inflammatory response and form fibrotic tissue, thus shrinking the hyperinflated lung. Autologous blood and AeriSeal are candidate potential bio-adhesives.

78. Morphologic Treatments of COPD Bronchial Rheoplasty : RheOx ® bronchial rheoplasty (Gala Therapeutics, San Carlos, CA, USA). It delivers short bursts of high-frequency electrical energy to the airway epithelium and submucosal tissue layers in order to target goblet cells. The procedure is performed in two separate treatments (one lung per treatment) with one month in between. Treatment is delivered from second- to seventh-generation airways. A multicenter clinical trial demonstrated significant improvements in CAT and SGRQ scores with no change in lung function parameters at 3 and 12 months.

79. Morphologic Treatments of COPD Metered Cryospray and Balloon Deobstruction : Metered Cryospray ( RejuvenAir , CSA Medical, Lexington, MA, USA) and balloon deobstruction ( Rezektor Balon , Istanbul, Turkey). They are two additional bronchoscopic treatment modalities specific to chronic bronchitis. Both are intended to destroy hyperplastic goblet cells via freezing and mechanical disruption, respectively. All three of these modalities are in the very early phase of research and development, having demonstrated quality-of-life improvements but little effect on cough or sputum production.

80. Lung Assist Devices : This is to build on the idea of ECMO which is not a feasible long-term assist as regard complications and bleeding.

81. Lung Bioengineering : There is interest in approaches for growing functional lung tissue ex vivo for potential use in transplantation and for the study of lung biology.

82. Lung Bioengineering : Lung Organoids Organoid technology is a powerful tool for studying lung developmental biology, cell–cell interactions, and cell–matrix interactions, and further serves as a pharmaceutical platform for screening and evaluating small molecules and other potential new therapeutic agents. Organoid technology has not been utilized to study defective epithelial cell biology in COPD. Classic methods for generating organoids involve the use of either pluripotent or tissue-derived stem cells. The generation of organoids from pluripotent stem cells requires a first step for the determination of the germ-layer (endoderm, mesoderm or ectoderm), followed by the sequential addition of specific signalling factors to differentiate into the tissue of interest.

83. Lung Bioengineering : Three-Dimensional Bioprinting and Lung-on-a-Chip This includes increasing ability to include live cells in the printing processes and creation of complex multilayered printed tissues. A growing number of studies are using these approaches for clinical management of diseases of the larger airways (trachea/ mainstem bronchi), usually in the setting of congenital defects, cancer, or trauma. Three-dimensional printing has had less progress in lung parenchymal applications as yet, in large part due to the current limitations on the printing resolution of current 3D bioprinters. Neither 3D bioprinting nor lung-on-a-chip has yet been extensively utilized to study lung epithelial or progenitor cells and/or matrix obtained from patients with COPD. The first lung-on-a-chip device was fabricated by Hugh and coauthors (2010), who recreated the blood–air barrier.

84. Lung Bioengineering : Organ Decellularization/Recellularization Organ decellularization has been one of the preferred strategies for the development of biomimetic lung 3D models. Lung donor cells are removed while the acellular 3D scaffold retaining the biochemical components, mechanical properties and the structural integrity of the native lungs (including the original vasculature) prevails. (simulating lung ECM)

85. Paolo Macchiarini

86. Lung Bioengineering : Paolo Macchiarini is a Swiss-born Italian thoracic surgeon and former regenerative medicine researcher who became known for research fraud and manipulative behavior . He has been convicted of research-related crimes in Italy and Sweden. He was considered a pioneer for using both biological and synthetic scaffolds seeded with patients' own stem cells as trachea transplants, Macchiarini has been accused of unethically performing experimental surgeries, even on relatively healthy patients, resulting in fatalities for seven of the eight patients who received one of his synthetic trachea transplants.

87. Thank You

88. This lecture was built on and copied from many review articles and books