Allogeneic mesenchymal stromal cells: Novel therapeutic option for mutated FLNA‐associated respiratory failure in the pediatric setting

Abstract

BackgroundMesenchymal stromal cell (MSC)‐mediated therapeutic effects have been observed in the treatment of lung diseases. For the first time, this treatment was used as rescue therapy in a pediatric patient with a life‐threatening respiratory syndrome associated with the filamin A (FLNA) gene mutation.MethodsA child with a new pathogenic variant of the FLNA gene c.7391_7403del (p.Val2464AlafsTer5), at the age of 18 months, due to serious and irreversible chronic respiratory failure, was treated with repeated intravenous infusions of allogeneic bone marrow (BM)‐MSCs. The child's respiratory condition was monitored. Immunologic studies before each MSC treatment were performed.ResultsNo acute adverse events related to the MSC infusions were observed. After the second infusion, the child's respiratory condition progressively improved, with reduced necessity for mechanical ventilation support. A thorax computed tomography (CT) scan showed bilateral recovery of the basal parenchyma, anatomical‐functional alignment and aerial penetration improvement. After the first MSC administration, an increase in Th17 and FoxP3+ T percentages in the peripheral blood was observed. After the second MSC infusion, a significant rise in the Treg/Th17 ratio was noted, as well as an increased percentage of CD20+/CD19+ B lymphocytes and augmented PHA‐induced proliferation.DiscussionMSC infusions are a promising therapeutic modality for patients in respiratory failure, as observed in this pediatric patient with an FLNA mutation. MSCs may have an immunomodulatory effect and thus mitigate lung injury; although in this case, MSC antimicrobial effects may have synergistically impacted the clinical improvements. Further investigations are planned to establish the safety and efficacy of this treatment option for interstitial lung diseases in children.

Pulmonary growth abnormalities as etiologies for pediatric pulmonary hypertension

“…FLNA mutations, we contend, are a prototype of a form of PGA with a clear genetic etiology and an emerging, broadening phenotype which should permit, when recognized, accurate diagnosis and appropriate treatment. Filamin A is a protein itself that plays an important role in lung structure and lung repair, perhaps explaining why this PGA phenotype tends to be more severe than most other types 6,7 …”

“…In terms of etiology, causes are clearly diverse. Patients with FLNA mutations have a clearly distinctive form of PGA with a defined genetic mutation in a protein important for neuronal migration and presumably as well for pulmonary development and lung repair 4‐7 …”

SARS-CoV-2 Exposed Mesenchymal Stromal Cell from Congenital Pulmonary Airway Malformations: Transcriptomic Analysis and the Expression of Immunomodulatory Genes

“…MSCs are also proposed in the treatment of congenital lung disorders in pediatrics [ 8 , 9 ]. A therapeutic approach using stem cells was tested after repeated administration of allogenic MSCs, which induced progressive improvement of respiratory conditions in children with interstitial lung disease [ 9 ].…”

“…MSCs are also proposed in the treatment of congenital lung disorders in pediatrics [ 8 , 9 ]. A therapeutic approach using stem cells was tested after repeated administration of allogenic MSCs, which induced progressive improvement of respiratory conditions in children with interstitial lung disease [ 9 ]. The regenerative process in the lung is dependent on a pool of lung MSCs that should allow lung regeneration with the maintenance of a normal architecture during the regeneration phase.…”

Do mesenchymal stromal cell infusions advance the understanding and treatment options of FLNA‐associated pulmonary disease?

“…Specifically, an enrichment in Th17 cells, FoxP3+ T cells, CD20+/CD19+ B lymphocytes in peripheral blood were noted, and enhanced phytohemagglutinin‐induced proliferation of peripheral blood mononuclear cells was seen. The authors speculate that the mechanisms by which the MSCs function include antimicrobial adjuvant or immune modulator …”