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View Full Version : Installment 45 - Ask the Doctor with Paolo Macchiarini, M.D., Ph.D



Jeannine
09-23-2011, 03:57 PM
About Paolo Macchiarini, M.D., Ph.D

Paolo Macchiarini, M.D., Ph.D., served as an advisor for the laryngeal transplant and assisted with the surgery. He is professor of regenerative surgery at the Karolinska Institutet and consultant on head and neck surgery in the department of otolaryngology at the Karolinska University Hospital in Stockholm, Sweden. Dr. Macchiarini's clinical interests include surgery for adult and pediatric complex tracheal diseases, lung, esophageal and mediastinal tumors, as well as intrathoracic, non-cardiac transplantation (lung, heart-lung and airways). His primary research interest involves the allotransplantation of airways, where he first described the technique of harvesting and implanting a laryngotracheal allograft in pigs and, more recently, tissue-engineered airway replacements. Dr. Macchiarini made transplant history in 2008 by using stem cells to help achieve the world’s first successful in-human transplantation of a tissue-engineered organ (windpipe) without immunosuppression. Dr Macchiarini makes his home in Spain.

Q: Do you think that stem cells alone will be able to regenerate lung tissue and reverse lung disease? What type of stem cells seem most promising?
A: Cell-based therapy might be a promising therapeutic option for lung diseases. It has been suggested that both autologous (self) and allogeneic (not-self) bone marrow-derived stem (mesenchymal stem cells, MSCs) and progenitor cells have great potential for the clinical use and may play a fundamental role in the near future for the treatment of patients with respiratory diseases.
These are the updated (Jungebluth P, Macchiarini P. Br Med Bull 2011;99:169-87) lung diseases that are under clinical trial evaluation using cell therapy:
Chronic obstructive pulmonary disease (COPD). A multicentre, double-blind, placebo-controlled phase II trial, conducted by Osiris, Inc. (NCT00683722), in which patients suffering from COPD are treated with ex vivo cultured adult human mesenchymal stem cells. Intermediate results showed no side-effects or toxicity, a reduced circulating level of C-reactive protein and an improved trend in the quality of life. The second clinical trial investigates the effect of the administration, viaperipheral vein, of bone marrow mononuclear cells (NCT01110252): the follow-up revealed a stable clinical condition, and amelioration in the quality of life.
Acute lung injury (ALI). A variety of animal models showed the significant impact of MSCs in ALI (reduced mortality, improved alveolar fluid clearance and/or changed inflammatory reactions) providing essential knowledge about the feasibility and efficiency of MSCs in ALI conditions. These results may already claim the translation of stem-based therapy into clinical practice for ALI or severe acute respiratory distress syndrome.
Pulmonary fibrosis (PF). It has been demonstrated that MSCs could have a protective effect and could be applied in early stages or as preventive strategy in conditions that are highly associated with the development of fibrosis, such as irradiation therapy. A nonrandomized single center, dose-ranging safety study of endobronchial infusion of adipose stem cells in idiopathic pulmonary fibrosis patients is currently on-going. So far, no clinically allergic reactions, disease acute exacerbation or infection have been revealed.
Cystic fibrosis (CF).Findings obtained in animal models showed a poor engraftment of applied stem cells, with no replacement of the damaged epithelial cells. Currently there are no clinical trials.
Asthma. It has been recently demonstrated that MSCs, modulating the immunological response in organism, could have a positive impact on allergic respiratory inflammation. This will bring forward MSCs clinical application in patients with severe and chronic allergic conditions.
Pulmonary hypertension (PH). Two recent trials of autologous intravenous endothelial progenitor cell infusions (NCT00257413, NCT00641836) were enrolled to evaluate the cell effects in terms of feasibility, safety and initial clinical outcome in patients with idiopathic pulmonary arterial hypertension. The researchers observed an ameliorated pulmonary artery pressure and vascular resistance. A Phase I trial (NCT00469027)is on-going to establish the safety of autologous progenitor cell-based gene therapy of heNOS in patients with severe pulmonary arterial hypertension refractory to conventional treatment. The patients showed a significant reduction of the pulmonary vascular resistance, raising hopes for clinical routine stem cell administration in PH. In spite of all these notable improvements and positive findings, it has been suggested that stem cells may contribute to systemic and pulmonary vascular remodeling in neonatal hypoxia, and, therefore, their clinical administration has to be evaluated accurately before applying routinely.

Q: Your ground breaking work with creating a new trachea using a patient's own stem cells seeded onto a synthetic scaffold was amazing. Could this technique be used to create new lungs or other organs within a person? If so, when might this type of therapy become available and will the cost be so high that most patients would not be able to afford it?
A:During the last two decades, most achievements have been obtained with tissue engineered simple or more complex tissues, such as bladder, skin and arteries. Bioengineering more complex three-dimensional architecture and structure (such as muscle, heart,liver and lungs) is a more difficult task. Regarding lungs, the use of artificial scaffolds (till now developed) resulted in limited clinical applicability because they neither fully replicate the complexity of the lung architecture or function, nor can they be easily implanted and appropriately anastomosed to the vascular and airway systems.
Recently, two different groups succeeded to experimentally (in rats) reseed decellularized lung scaffolds, showing initial physiological and functional properties of these engineered lungs. Even if we are far behind right now, an entire functional tissue engineered lung, may be possible with these new technologies.

Q: I have COPD and asthma as well. Are there certain genes that have been identified that make some people susceptible to this disease? If so, can you tell me which genes they are? Would some kind of gene therapy be required along with stem cells for a cure for lung diseases?
A: COPD is a multifactorial disease that may be influenced by genetic as well as environmental factors resulting in a complex genotype-environment interaction. Studies have demonstrated that several genes with small effects, rather than a single major gene, seem to be of importance for the development of COPD (Al-Jamal R et al Expert OpinBiolTher 2005; 5:333-46; Sakao S and Tatsumi K. Respirology. 2011 Aug 8. doi: 10.1111/j.1440-1843.2011.02032.x.).
Some of the genetic factors that resulted to determine COPD development are:
Alpha1-antitrypsin (AAT):severe deficiency of AAT is the only proven genetic risk factor for COPD
Tumor necrosis factor (TNF)-α: an increased prevalence for the single nucleotide polymorphism (SNP)-308 in the promoter region of theTNF-α gene resulted in patients with COPD compared to controls in Japanese population (not confirmed in Caucasian population).
Matrix metalloproteinase 9 (MMP9): a functional SNP of the MMP9 gene promoter region was found to be associated with COPD both in Chinese and Japanese populations (but not in a Canadian population).
Alpha 1-antichymotrypsin (SERPINA3): two functional SNPs in the SERPINA3 gene was found to be associated with low α1-antichymotrypsin levels and COPD in a Swedish population (but not in an Italian study).
Glutathione S-transferases (GST): one SNP in GSTP1 was found to be associated with a rapid decline of FEV1, as well as low baseline lung function in a Canadian population.
Microsomal epoxide hydrolase (mEH): a polymorphisms, Y113H, recent results show it to be associated with a higher risk for development of COPD.
Alphanicotinicacetylcholine receptor(CHRNA): two SNPs at the CHRNA 3/5 locus recently found to be associated with COPD. However, it remains unknown whether SNPs in that region have a direct effect on the development of COPD or merely mediate smoking habits in the patients with COPD.
All the key mediators of COPD pathology and the genetic polymorphism can be classified as affectors and therefore, intervention using any single one of them is perhaps of very limited therapeutic value. So far, only one clinical study (Phase I) for COPD-related gene therapy has been for AAT deficiency. The therapy has shown no inflammatory response, even if the AAT levels did not increase to normal levels suggesting a protective effect.

Q: What causes dypsnea and what does it take to subdue it?
A: The term “dyspnea” comes from the latin “dyspnoea” and literally means “disordered breathing”.
Based on the American Thoracic Society definition, dyspnea is a "subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses."
In simple words, dyspnea results when there’s a mismatch between the need for ventilation and the physical breathing that is occurring. Dyspnea is a common symptom in a wide range of diseases: first of all cardiac or respiratory disorders, but also neurological, musculoskeletal, endocrine, hematologic, and psychiatric disorders. Actually, dyspnea is responsible for about 4% of all admissions to the emergency department. The most common pulmonary causes of dyspnea are: chronic obstructive pulmonary disease (COPD), asthma, pneumonia and pneumothorax. Sometimes dyspnea is the first symptom of lung cancer, such as in case of a massive paraneoplastic pleural effusion. Obviously the primary treatment of dyspnea is directed at its underlying cause. In case of dyspnea secondary to COPD, physiotherapy plays a crucial role and includes active assisted cough techniques, volume augmentation such as breath stacking, education about body position and movement strategies to facilitate breathing.

Q: What do you think would be the best way to deliver stem cells to the lungs for Idiopathic Pulmonary Fibrosis? Is it possible to create new lung tissue?
If there is regeneration of the lung tissue with stem cell therapy for IPF, what happens to the lungs after the regeneration? Would they continue to scar?
A: Currently, the application of MSCs as therapeutic strategies in IPF is still in its infancy and remains exploratory. In my opinion, and based on results obtained using COPD rat models, the intratracheal administration via an endotracheal tube under general anesthesia could be the best way to make cell-based therapy clinically practicable and optimize cell engraftment. In support of this, the preliminary results obtained in a nonrandomized single center, dose-ranging safety study of endobronchial infusion of adipose stem cells in IPF patients, which is still ongoing, seem promising.
Animal studies demonstrated that, although the MSC infusion resulted in low level of cell engraftment and differentiation, their administration led to a significant attenuation of inflammation and fibrosis, suggesting that MSCs act as modulators of inflammation and fibrosis through the release of paracrine anti-inflammatory and/or antifibrotic factors and not through their ability to differentiate (and create new lung tissue).

Q: Why are there so few clinical trials for COPD, IPF, cystic fibrosis and other lung diseases that use stem cells? Is there any kind of worldwide collaboration going on because there isn't much available that I know of except private clinics that are charging a lot and delivering a little. Lung disease seems to be the forgotten disease.
A: So far, efforts by researchers to apply cell-based therapies for the treatment of lung diseases have been severely hampered by safety and ethical concerns mainly arising from the yet unknown disease pathology/immunopathology and the need for better understanding of the mechanisms underlying pleiotropic properties of MSCs. Indeed there is still a lack of exact knowledge concerning in vivo cell differentiation and therefore an incautious clinic application of MSCs is avoided. However based on the several animal studies performed in the last years, first clinical trials have been designed (for details see answer to Question 1).

Q: Since research is now showing that a great percentage of patients who have COPD actually die of heart disease, would it be wise to get stem cell therapy every so often just to try to keep your heart healthy? Since a lot of treatments use IV infusions, it seems like that method would just send the stem cells to wherever they are needed the most. Your comments please.
A:Different animal studies have demonstrated that in vitro expanded MSCs home to damaged tissues and contribute to the repair process, supporting tissue healing and regeneration. Moreover, it has been demonstrated that the therapeutic actions of MSCs engrafted in injured lungs are the result of paracrine effects: MSCs embolized in the mouse lung with myocardial infarction demonstrated to enhance myocardial repair without cardiac engraftment by an upregulation of the expression, and subsequent secretion, of the anti-inflammatory protein TNF-α-induced protein-6.
Our results, obtained in COPD rat models treated with intratracheal MSC administration, demonstrated that the effect of the MSC application was not only restricted to the lung and its hemodynamics but also systemical impact was detected. However, in my opinion,the improvement of cardiac function and RV hypertrophy might be mostly explained as a consequence of decreased pulmonary hypertension and pulmonary vascular resistances. In simple words, if you succeed to cure the lungs you will improve and reverse the pathological status of the heart, and this will be then no more a cause of death.

Q: Are there any risks associated with being treated with your own stem cells? There are a lot of different methods. Is it more likely that the method in which they are given back to a person or the way they are taken out and processed that would cause the most problems or can they both be risky? Can having frequent treatments with high stem cell counts cause problems such as an increased risk for cancer?
A: Based on our clinical experience with a fully tissue engineered windpipe seeded with autologous MSCs with a follow-up of more than 3 years, in which we were unable to detect cancer development, we may say that the administration of MSCs in inflammatory or damaged conditions does not lead to an uncontrolled cell proliferation or differentiation. However, the effects of administrated cells can differ significantly in relation to the variability of stem cells from different sources (bone marrow, umbilical blood, tissue derived stem cells), inter-donor variability (even from same sources), intrinsic/extrinsic mechanisms and factors (site of cell administration) and/or the necessity of the in vitro culture. As a consequence, at this moment we cannot exclude cancer development and further studies are needed to answer this question.

Q: There are a lot of people dying from all kinds of disease, but lung disease is one of the top killers. When a person such as the one who needed the new windpipe got to try experimental treatment, how was he selected? Why can't similar experimental treatments be tried with consenting individuals who may be running out of time and do not even qualify for a lung transplant? Is it because no one has figured out how best to treat lung disease?
A: The patients treated with bioengineered airway transplant had used already all therapeutical options and the only possible alternative curative was identified in the tracheal transplant. This has been possible because the trachea results to be a relatively simple and hollow complex tissue, and was the ideal starting point for respiratory organ engineering. Given the complex three-dimensional architecture and structure-function relationships of the lung as well the multiple differentiated lung cell types (>40), ex vivo lung bioengineering is a potentially daunting task nonetheless there has been significant progress in several areas. Recently, two different groups succeeded in using experimentally (in rats) decellularized reseeded lung scaffolds, showing initial physiological and functional properties of these engineered lungs. Studies are trying to evaluate whether stem or progenitor cells can form airway or alveolar-like structures when cultivated in de-cellularized whole lungs or further whether stem or progenitor cells cultured in such fashion can be utilized for functional lung regeneration in vivo. Lung tissue bioengineering with stem cells is still in this moment in its infancy but it is projected to be an area of intense investigation.

Q: What is the most promising treatment or medication you know of that may become available to those with respiratory problems in the next 5 years?
A: In my opinion in the next five years, the development of the in vivo tissue engineered approach (based on an appropriate scaffold and a pharmacological intervention to boost progenitor cell, recruitment and commitment and thereby promote tissue regeneration), already used for tracheal transplant, will provide a therapeutic option and eventually a cure for patients with serious clinical airway disorders. In a dream world, however, I would like to stimulate our “dormant” stem cells present in our body to help repair damaged organs without reaching the necessity to replace them.