Molecular therapies exploit understanding of pathogenic mechanisms to reconstitute impaired gene function or manipulate flawed RNA expression. These therapies include 1) RNA interference by antisense oligonucleotides, 2) mRNA modification using small molecules, and 3) gene replacement therapy, the viral-mediated intracellular delivery of exogenous nucleic acids to reverse a genetic defect. Several molecular therapies are approved for treating spinal muscular atrophy (SMA), a recessive genetic disorder caused Survival Motor Neuron (SMN)1 gene mutations. SMA involves degeneration of lower motor neurons, which leads to progressive muscle weakness, hypotonia, and hypotrophy. Onasemnogene abeparvovec is a gene replacement therapy for SMA that uses Adeno Associated Virus delivery of functional SMN1 cDNA to motor neurons. Two other molecular therapies modulate SMN2 transcription: nusinersen, an antisense oligonucleotide, and risdiplam, a small molecule designed to modify faulty mRNA expression. The most suitable individualized treatment for SMA is not established. Here, we describe remarkable clinical improvement in a 4-month-old patient with SMA type 1 who received onasemnogene abeparvovec therapy. This case represents an explanatory bridge from bench to bedside with regard to therapeutic approaches for genetic disorders in neurology. Knowledge of the detailed mechanisms underlying genetic neurological disorders, particularly monogenic conditions, is paramount for developing tailored therapies. When multiple disease-modifying therapies are available, early genetic diagnosis is crucial for appropriate therapy selection, highlighting the importance of early identification and intervention. A combination of drugs, each targeting unique genetic pathomechanisms, may provide additional clinical benefits.

Bridging the Gap : Gene Therapy in a Spinal Muscular Atrophy Type 1 Patient / G. Costamagna, A. Govoni, A. Wise, S. Corti. - In: NEUROLOGY. - ISSN 0028-3878. - 99:21(2022 Nov 01), pp. 952-956. [10.1212/WNL.0000000000201294]

Bridging the Gap : Gene Therapy in a Spinal Muscular Atrophy Type 1 Patient

G. Costamagna
Primo
;
A. Govoni
Secondo
;
S. Corti
Ultimo
2022

Abstract

Molecular therapies exploit understanding of pathogenic mechanisms to reconstitute impaired gene function or manipulate flawed RNA expression. These therapies include 1) RNA interference by antisense oligonucleotides, 2) mRNA modification using small molecules, and 3) gene replacement therapy, the viral-mediated intracellular delivery of exogenous nucleic acids to reverse a genetic defect. Several molecular therapies are approved for treating spinal muscular atrophy (SMA), a recessive genetic disorder caused Survival Motor Neuron (SMN)1 gene mutations. SMA involves degeneration of lower motor neurons, which leads to progressive muscle weakness, hypotonia, and hypotrophy. Onasemnogene abeparvovec is a gene replacement therapy for SMA that uses Adeno Associated Virus delivery of functional SMN1 cDNA to motor neurons. Two other molecular therapies modulate SMN2 transcription: nusinersen, an antisense oligonucleotide, and risdiplam, a small molecule designed to modify faulty mRNA expression. The most suitable individualized treatment for SMA is not established. Here, we describe remarkable clinical improvement in a 4-month-old patient with SMA type 1 who received onasemnogene abeparvovec therapy. This case represents an explanatory bridge from bench to bedside with regard to therapeutic approaches for genetic disorders in neurology. Knowledge of the detailed mechanisms underlying genetic neurological disorders, particularly monogenic conditions, is paramount for developing tailored therapies. When multiple disease-modifying therapies are available, early genetic diagnosis is crucial for appropriate therapy selection, highlighting the importance of early identification and intervention. A combination of drugs, each targeting unique genetic pathomechanisms, may provide additional clinical benefits.
Settore MED/26 - Neurologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
WNL.0000000000201294.full.pdf

embargo fino al 01/11/2023

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1.42 MB
Formato Adobe PDF
1.42 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
952.full.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 531.41 kB
Formato Adobe PDF
531.41 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

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/2434/944638
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact