Administration of gene replacement therapy in patients with spinal muscular atrophy 5q type 1 with chronic nosocomial bronchopulmonary infection

Introduction. Spinal muscular atrophy (SMA) 5q is a severe hereditary neuromuscular disorder, one of the serious manifestations of which is the development of progressive respiratory insufficiency. The administration of pathogenetic therapy leads to decreased symptoms of respiratory failure, which reduces the risk of lethal outcome and is fundamental for stabilizing the progression of physical development and new motor skills in SMA patients.

The aim — to present experience of onasmenogen abeparvovec (OA) gene replacement therapy (GRT) in patients with SMA type 1 and severe respiratory failure combined with chronic bronchopulmonary infection caused by nosocomial multidrug-resistant microflora in real clinical practice.

Materials and methods. Five patients with SMA type 1 and respiratory failure of second degree complicated by chronic bronchopulmonary infection were enrolled in this study. All patients were performed a comprehensive clinical, laboratory, and radiologic examination before and for two years after GRT OA administration toof evaluate the severity of respiratory disturbances. The efficiency of OA therapy was estimated with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), and motor development was assessed by the Hammersmith Infant Neurologic Examination Part 2 (HINE-2).

Results. The medical records of 5 (four boys and one girl ) patients with SMA type 1 at the mean age of 19 months (13 to 27 months) at the time of GRT OA administration were analyzed, of them. All patients had been treated with a different type of pathogenetic therapy before GRT OA. After the preventive, personalized antibacterial therapy, all patients experienced GRT OA administration without exacerbation of chronic bronchopulmonary infection, despite hormonal therapy in an immunosuppressive dose (1 mg/kg). There were no lethal outcomes during two years after GRT OA. Over the first year, patients demonstrated a progressive increase in motor skills with further stabilization, but during the second year of follow-up, two patients showed moderate regression of motor skills after pneumonia. One of five patients had a positive lung function dynamics and eradication of highly pathogenic bacterial microflora from the respiratory tract.

Conclusions. It is comparatively safe to administer GRT OA in children with SMA type 1 and chronic respiratory infection. However, changing pathogenetic therapy to GRT OA in the cases we presented did not have clinically significant advantages and required more careful patient preparation. Additional risks associated with the occurrence of immune-mediated adverse events due to concomitant hormonal therapy, which can be avoided on other types of pathogenetic therapy, should be considered.

Compliance with ethical standards. The study was approved by the local Ethics Committee of the Pirogov Russian National Research Medical University (Protoсol No. 226 of 20.02.2023). The patients’ legal representatives signed informed consent on the use of onasemnogene abeparvovec, all were informed about possible side effects of the drug and risks of using hormonal therapy against the background of chronic bronchopulmonary infection.

Contribution:
Papina Yu.O. — research design, patient supervision, study coordination, collection of materials and data processing, text writing, review of publications on the topic of the article;
Artemyeva S.B. — study coordination, analysis of the obtained data, article editing;
Belousova E.D. — study coordination;
Volynets G.V. — patient supervision, article editing;
Dyakova S.E. — patient supervision, analysis of the obtained data, article editing;
Rastegina S.E. — article editing;
Komarova O.N. — patient supervision, article editing;
Melnik E.A. — analysis of the obtained data, article editing;
Podgorny A.N. — patient supervision;
Vlodavets D.V. — study coordination, article editing.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: August 5, 2024

Accepted: September 5, 2024

Published: October 30, 2024

1. Ross L.F., Kwon J.M. Spinal muscular atrophy: past, present, and future. Neoreviews. 2019; 20(8): e437–51. https://doi.org/10.1542/neo.20-8-e437

2. D’Amico A., Mercuri E., Tiziano F.D., Bertini E. Spinal muscular atrophy. Orphanet J. Rare Dis. 2011; 6: 71. https://doi.org/10.1186/1750-1172-6-71

3. Kolb S.J., Kissel J.T. Spinal muscular atrophy. Neurol. Clin. 2015; 33(4): 831–46. https://doi.org/10.1016/j.ncl.2015.07.004

4. Verhaart I.E.C., Robertson A., Wilson I.J., Aartsma-Rus A., Cameron S., Jones C.C., et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - A literature review. Orphanet J. Rare Dis. 2017; 12(1): 124. https://doi.org/10.1186/s13023-017-0671-8

5. Cances C., Vlodavets D., Comi G.P., Masson R., Mazurkiewicz-Bełdzińska M., Saito K., et al. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J. Rare Dis. 2022; 17(1): 300. https://doi.org/10.1186/s13023-022-02455-x

6. Finkel R.S., McDermott M.P., Kaufmann P., Darras B.T., Chung W.K., Sproule D.M., et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9): 810–7. https://doi.org/10.1212/WNL.0000000000000741

7. Hjartarson H.T., Nathorst-Böös K., Sejersen T. Disease modifying therapies for the management of children with Spinal Muscular Atrophy (5q SMA): An update on the emerging evidence. Drug Des. Devel. Ther. 2022; 16: 1865–83. https://doi.org/10.2147/DDDT.S214174

8. Reilly A., Chehade L., Kothary R. Curing SMA: Are we there yet? Gene Ther. 2023; 30(1-2): 8–17. https://doi.org/10.1038/s41434-022-00349-y

9. Mikhalchuk K., Shchagina O., Chukhrova A., Zabnenkova V., Chausova P., Ryadninskaya N., et al. Pilot program of newborn screening for 5q spinal muscular atrophy in the Russian Federation. Int. J. Neonatal. Screen. 2023; 9(2): 29. https://doi.org/10.3390/ijns9020029

10. Fauroux B., Khirani S., Griffon L., Teng T., Lanzeray A., Amaddeo A. Non-invasive ventilation in children with neuromuscular disease. Front. Pediatr. 2020; 8: 482. https://doi.org/10.3389/fped.2020.00482

11. Alekseeva O.V., Shnayder N.A., Demko I.V., Petrova M.M. Obstructive apnea/hypopea syndrome of sleep: criteria of severity, pathogenesis, clinical manifestations and methods of diagnosis. Sibirskii meditsinskii zhurnal (Irkutsk). 2016; 140(1): 91–97. https://elibrary.ru/wefkcv (in Russian)

12. Hull J., Aniapravan R., Chan E., Chatwin M., Forton J., Gallagher J., et al. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax. 2012; 67(Suppl. 1): i1–40. https://doi.org/10.1136/thoraxjnl-2012-201964

13. Hoang S., Georget A., Asselineau J., Venier A.G., Leroyer C., Rogues A.M., et al. Risk factors for colonization and infection by Pseudomonas aeruginosa in patients hospitalized in intensive care units in France. PLoS One. 2018; 13(3): e0193300. https://doi.org/10.1371/journal.pone.0193300

14. Venier A.G., Leroyer C., Slekovec C., Talon D., Bertrand X., Parer S., et al. Risk factors for Pseudomonas aeruginosa acquisition in intensive care units: A prospective multicentre study. J. Hosp. Infect. 2014; 88(2): 103–8. https://doi.org/10.1016/j.jhin.2014.06.018

15. Lazareva A.V., Tchebotar I.V., Kryzhanovskaya O.A., Tchebotar V.I., Mayanskiy N.A. Pseudomonas aeruginosa: pathogenicity, pathogenesis and diseases. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya. 2015; 17(3): 170–86. https://elibrary.ru/uhpuwp (in Russian)

16. Abban K., Ayerakwa E.A., Mosi L., Isawumi A. The burden of hospital acquired infections and antimicrobial resistance. Heliyon. 2023; 9(10): e20561. https://doi.org/10.1016/j.heliyon.2023.e20561.

17. Farrar M.A., Park S.B., Vucic S., Carey K.A., Turner B.J., Gillingwater T.H., et al. Emerging therapies and challenges in spinal muscular atrophy. Ann. Neurol. 2017; 81(3): 355–68. https://doi.org/10.1002/ana.24864

18. Stettner G.M., Hasselmann O., Tscherter A., Galiart E., Jacquier D., Klein A. Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study. BMC Neurol. 2023; 23(1): 88. https://doi.org/10.1186/s12883-023-03133-6

19. Day J.W., Mendell J.R., Mercuri E., Finkel R.S., Strauss K.A., Kleyn A., et al. Clinical trial and Postmarketing safety of onasemnogene abeparvovec therapy. Drug Saf. 2021; 44(10): 1109–1119. https://doi.org/10.1007/s40264-021-01107-6

20. Blair H.A. Onasemnogene abeparvovec: a review in spinal muscular atrophy. CNS Drugs. 2022; 36(9): 995–1005. https://doi.org/10.1007/s40263-022-00941-1

21. Mendell J.R., Al-Zaidy S., Shell R., Arnold W.D., Rodino-Klapac L.R., Prior T.W., et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 2017; 377(18): 1713–22. https://doi.org/10.1056/nejmoa1706198

22. Day J.W., Finkel R.S., Chiriboga C.A., Connolly A.M., Crawford T.O., Darras B.T., et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021; 20(4): 284–93. https://doi.org/10.1016/S1474-4422(21)00001-6

23. Mercuri E., Muntoni F., Baranello G., Masson R., Boespflug-Tanguy O., Bruno C., et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021; 20(10): 832–41. https://doi.org/10.1016/S1474-4422(21)00251-9

24. Chand D., Novartis R.S., Diab K., Kenny D., Tukov F.F. Review of cardiac safety in onasemnogene abeparvovec gene therapy: translation from preclinical to clinical findings. Res. Sq. Preprint. https://doi.org/10.21203/rs.3.rs-1979632/v1

25. Artem’eva S.B., Belousova E.D., Vlodavets D.V., Voronin S.V., Glotov A.S., Guzeva V.I., et al. Consensus on gene replacement therapy for the treatment for spinal muscular atrophy (release № 2). Nevrologicheskii zhurnal im. L.O. Badalyana. 2023; 4(2): 64–73. https://doi.org/10.46563/2686-8997-2023-4-2-64-73 https://elibrary.ru/cgpzyn (in Russian)

26. Clinical recommendations. Cystic fibrosis (cystic fibrosis); 2021. (in Russian)

27. Glanzman A.M., Mazzone E., Main M., Pelliccioni M., Wood J., Swoboda K.J., et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): Test development and reliability. Neuromuscul. Disord. 2010; 20(3): 155–61. https://doi.org/10.1016/j.nmd.2009.11.014

28. Bishop K.M., Montes J., Finkel R.S. Motor milestone assessment of infants with spinal muscular atrophy using the hammersmith infant neurological Exam – Part 2: Experience from a nusinersen clinical study. Muscle Nerve. 2018; 57(1): 142–6. https://doi.org/10.1002/mus.25705

29. Pierzchlewicz K., Kępa I., Podogrodzki J., Kotulska K. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol. Open. 2021; 8: 2329048X2110087. https://doi.org/10.1177/2329048x211008725

30. Friese J., Geitmann S., Holzwarth D., Müller N., Sassen R., Baur U., et al. Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec – a single centre experience. J. Neuromuscul. Dis. 2021; 8(2): 209–16. https://doi.org/10.3233/JND-200593