Modulation of SMN2, the 'Back-Up' Gene: Through Antisense Oligonucleotides (ASOs)
Modulation of the SMN2 ‘Back-up’ Gene
For our lower motor neurons to function and remain healthy, our cells need to produce the survival motor neuron (SMN)
protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene.
The SMN2 gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. For this reason, SMA is caused only by mutations in the SMN1 gene and not SMN2, and also why SMN2 is often called the SMN ‘back-up’ gene.
Anyone who has SMA has at least one copy of the SMN2 gene. Individuals can have multiple copies of SMN2, and, in general, it seems that those with more copies have a less severe form of SMA.
Most of the SMN protein made by SMN2 (about 90%) is missing an important piece called exon 7. The remaining 10% of the protein produced by SMN2 includes exon 7 and is the same as that made by SMN1. A number of treatment strategies that target SMN2 to make more functional SMN protein are being explored; they aim to do this in one of three main ways:
- Correct SMN2 splicing, allowing SMN2 to more efficiently produce functional SMN protein:
- Increase the protein production from SMN2 leading to more functional SMN protein.
- Stabilise the functional SMN protein made by SMN2 and therefore make it last longer.
Nusinersen is not a classical gene therapy because the treatment does not directly modify a person’s genes. However, it is sometimes regarded as a 'gene therapy' as it impacts how the messenger RNA from the SMN2 gene is used to make SMN protein.
Antisense oligonucleotide drugs are small snippets of synthetic genetic material that bind ribonucleic acid (RNA). They are often described as molecular patches because they can be specifically designed to target and affect how a particular gene is read. ASOs have great potential for SMA, because they can accurately target the SMN2 gene to essentially convert it into the SMN1 gene, i.e. they are small molecules “patching-up” SMN2 to act more like SMN1. They do this by binding to the RNA template made by SMN2 and enhancing the inclusion of exon 7 into the SMN protein. (See the above link for a more detailed explanation).
For an up to date view of progress see:
The Drug Pipeline
First patient treated in Biogen’s global RESPOND study of nusinersen, following treatment with Zolgensma™
Independent Real-World Study Demonstrates Significant Improvements for Adults who have SMA Type 3, Treated with Nusinersen
Biogen to Initiate Phase 4 Study Evaluating Benefit of Spinraza® in Patients Treated With Zolgensma®
Further Small Studies Support the Use of Nusinersen for SMA Treatment in Adults
FURTHER POSITIVE RESULTS IN NURTURE STUDY WITH PRE-SYMPTOMATIC SMA PATIENTS TREATED WITH NUSINERSEN
FIRST PATIENT IN BIOGEN DEVOTE TRIAL TREATED WITH HIGHER NUSINERSEN DOSE
Study Shows Nusinersen is Safe and Effective for SMA Treatment in Adults
Biogen Communicates Updated NURTURE Study Results for the European Community
Two new studies show positive effects of nusinersen in later-onset SMA
PRE-SYMPTOMATIC INFANTS TREATED WITH SPINRAZA™ ACHIEVE MOTOR MILESTONES MORE CONSISTENT WITH NORMAL DEVELOPMENT
Data Published in Neurology Suggest Long-Term Benefits of Spinraza™ Treatment in Later-Onset SMA
Summary and comparison of results to date for nusinersen and gene therapy (Avexis-101)
Updates on nusinersen/Spinraza Trials at the World Muscle Society Meeting
Update on CHERISH and NURTURE clinical trials of Spinraza
BIOGEN ANNOUNCES EAP FOR NUSINERSEN WILL NOT EXTEND MORE WIDELY THAN SMA TYPE 1
CLINICIANS' OPEN LETTER ABOUT THE EAP FOR CHILDREN WITH SMA TYPE 1 IN THE UK
BIOGEN UPDATE ON THE NUSINERSEN EAP FOR THOSE WITH SMA TYPE 1 IN THE UK
UPDATE ON THE UK EXPANDED ACCESS PROGRAMME (EAP) FOR NUSINERSEN FOR CHILDREN WITH SMA TYPE 1
BIOGEN AND SMA EUROPE PROVIDE COMMUNITY UPDATE ON NUSINERSEN
WORKING TO SPEED UP THE NUSINERSEN (SPINRAZA) APPRAISAL BY THE EUROPEAN MEDICINES AGENCY (EMA)
SPINRAZA (NUSINERSEN) APPROVED BY FDA IN THE US
Novel Antisense Therapy Removes the Brakes on SMN Protein Production
Nusinersen Phase 2 Trial Results Published in The Lancet
FDA accept Nusinersen for Priority Review
MOLECULAR “HOMING DEVICES” DRASTICALLY IMPROVE SMA THERAPY
Ionis Pharmaceuticals update on Phase II study of Nusinersen
Biogen and Ionis Pharmaceuticals Provide Update on Nusinersen (Formerly Known as ISIS-SMNRx)
ISIS PHARMACEUTICALS CHANGES ITS NAME TO IONIS PHARMACEUTICALS
ISIS PHARMACEUTICALS INITIATES NEW ISIS-SMNRX EXTENSION STUDY, SHINE
Biogen and Isis Pharmaceuticals provide community update on ISIS-SMNRx
Isis pharmaceuticals announces latest update from ongoing Phase II Trial
IMPORTANT SAFETY UPDATE ON SMN2 SPLICE-MODIFYING DRUG RG7800
ISIS PHARMACEUTICALS INITIATES SECOND PHASE III TRIAL OF ISIS-SMNRX
ISIS-SMNRX PHASE II TRIAL RESULTS RELEASED
ISIS PHARMACEUTICALS INITIATE PHASE III TRIAL OF ISIS-SMNRX
ISIS PHARMACEUTICALS ANNOUNCES INTERIM RESULTS OF ISIS-SMNRX PHASE II TRIALS
ISIS PHARMACEUTICALS INITIATES A PHASE IB/IIA TRIAL OF ISIS-SMNRX IN SMA PATIENTS
BIOGEN IDEC ENTERS GLOBAL COLLABORATION WITH ISIS PHARMACEUTICALS FOR ANTISENSE SMA DRUG DEVELOPMENT
ASOs were used in mice to show that it is likely that SMN protein levels will need to be restored throughout the body, and not just the nervous system, in order to have the best chances of successfully treating the disease in patients.
SMN PROTEIN: NOT JUST IMPORTANT FOR THE NERVOUS SYSTEM
ISIS PHARMACEUTICALS ANNOUNCE PHASE IA CLINICAL TRIAL IN YOUNG SMA PATIENTS
NOVEL ANTISENSE THERAPY REMOVES THE BRAKES ON SMN PROTEIN PRODUCTION