Peptide conjugated oligonucleotides for a phase I/IIa clinical trial in Spinal Muscular Atrophy

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics


Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, arising from loss-of-function of the SMN1 gene. Mutations in SMN1 result in motor neuron degeneration, accompanied by peripheral manifestations including skeletal muscle atrophy. SMA is rare autosomal recessive disease with an incidence of ~1:10,000 live births. Most affected SMA infants typically have a severe form of the disease with a mean life expectancy of ~2 years in age (SMA Type I). However children with less severe disease (SMA Type II and III) can survive beyond 2 years but with severe mobility problems and comorbidities (respiratory insufficiency; scoliosis; failure to thrive) that limit normal functioning and survival. SMA severity relates directly to the level of functional SMN protein that a patient produces. A closely related gene to SMN1 is SMN2, although this gene typically only produces ~10% of fully functional SMN protein. However some SMA patients have additional copies of the SMN2 gene as the copy number of this latter gene is polymorphic in the general population, and hence can produce more functional SMN protein. This mitigates disease severity and such patients typically have a milder disease course.

Most SMN2 gene product is not functional because the gene generates two distinct mRNAs via alternative splicing i.e. most of the mRNA lacks exon 7 and generates only partially functional protein. The most effective therapy currently for SMA is splice modification of the SMN2 pre-mRNA through use of SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) to increase levels of SMN protein. SSOs are single-stranded, DNA-like molecules that can bind to and alter the processing of SMN2 pre-mRNA to generate functional copy of the gene. A SSO (Nusinersen) which modifies SMN2 splicing to generate functional SMN protein has recently been approved for clinical use by the FDA and EMA. While this represents a major development for SMA, this first generation SSO does not penetrate the blood brain barrier (BBB) and is therefore administered through repeated invasive intrathecal injections into the fluid around the spinal cord. This is necessary for adequate spinal cord drug delivery but is not practical as a long-term therapy and moreover it also fails to treat systemic features of the disease, especially important in severe cases.

The major challenge to successful development of an SSO therapy for SMA is systemic delivery of the SSO drug to all affected tissues involved in disease pathogenesis in addition to motor neurons, including peripheral tissues such as skeletal muscle and neuromuscular junctions, liver and autonomic nerves. We have developed a novel platform technology based on short cell penetrating peptides, which when attached to SSOs via direct chemical attachment provide highly effective penetration into cells and into tissues such as the brain and spinal cord and muscles which are exceptionally difficult to reach for large SSO drugs.

The major OBJECTIVE of the current project is therefore to identify, develop and test an advanced NEXT GENERATION peptide-SSO for SMA. To achieve this we will:

- Select the most suitable peptide based on further study of ~5 peptide-SSO candidates to determine their activity and safety properties in mice

- Take this lead peptide-SSO and carry out a full safety assessment of the drug in two species (rats and non-human primates) as required by the Medicines and Healthcare Regulatory Agency, in order to obtain approval to undertake a clinical trial in SMA patients

- Carry out a first-in-man phase I/IIa clinical trial in 12 less severely affected Type II and III SMA patients, who represent the most prevalent SMA patients, many of whom are not eligible candidates for intrathecal administration of drugs due to spinal abnormalities. This clinical trial will determine safety and inital effectiveness of the drug and will be a prelude to more detailed studies in larger numbers of patients

Technical Summary

SPINAL MUSCULAR ATROPHY (SMA) is a leading genetic cause of infant mortality due to progressive lower motor neuron death leading to muscle weakness. SMA is caused by loss of the ubiquitously expressed SMN1 gene. Patients carry the very closely related gene SMN2 which is only partially functional due to its alternative splice exclusion of exon 7. SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) are single-stranded, steric block oligonucleotides which, when directed toward splice sites of pre-mRNA, block binding of the splice enhancing or silencing proteins. A SSO (Nusinersen) which modifies SMN2 splicing to facilitate exon 7 inclusion to generate functional SMN protein has recently been approved for clinical use by the FDA and EMA. This first generation SSO does not penetrate the blood brain barrier (BBB) and is therefore administered through repeated invasive intrathecal injections. This is necessary for adequate spinal cord drug delivery but is not practical as a long-term therapy and also fails to treat systemic features of the disease, especially important in severe cases. We have developed advanced NEXT GENERATION SSOs comprising a peptide-conjugated SSO platform permitting effective systemic SSO delivery to essential peripheral tissues (e.g. skeletal muscle), brain and spinal cord and under a current MRC DPFS award have undertaken rigorous preclinical development and identified candidate peptide-PMOs (PPMO). We now propose to finalise preclinical work by defining therapeutic index in order to select lead and back-up PPMO candidates for clinical development. Lead and back-up PPMO clinical candidates will then undergo appropriate PK/PD and toxicology assessment in two species (rats and non-human primates) to allow MHRA clinical trial protocol approval. The lead PPMO compound will subsequently be evaluated for safety, tolerability and exploratory efficacy in a Phase I/IIa clinical trial in SMA patients.

Planned Impact

The project will undertake clinical development of a systemically delivered, NEXT GENERATION peptide-SSO therapy for the fatal, neuromuscular disease, spinal muscular atrophy (SMA), leading to evaluation of a lead peptide-SSO drug in a phase I/IIa clinical trial in 12 Type II/III SMA patients to determine safety and exploratory efficacy. If successful this work will advance the state-of-the-art which is currently a first generation SSO drug, administered by repeated, invasive intrathecal administration, and is thus likely to have high impact with numerous individuals, groups and organisations benefitting including:

- ACADEMIC BENEFICIARIES will include the PI, the Project Team, the PI's and Co-I's UK collaborators (e.g. the MDEX Consortium) and non-UK international collaborators. Other academic beneficiaries will include research groups working in the SMA and related neuromuscular, motor neuron and neurodegenerative disease fields, the oligonucleotide therapeutics field, and those working on technologies for or with interests in macromolecular drug delivery to the brain.

- NON-ACADEMIC BENEFICIARIES will include SMA patients, their families and advocacy organisations that support SMA patients and research, and those in the biotechnology, pharmaceutical and investment sectors that have interests in relation to SMA, oligonucleotide therapeutics and to the therapy of rare diseases more generally.

ACADEMIC BENEFICIARIES will benefit in the short term from direct knowledge outputs including publications and other forms of research communication. Knowledge gained will inform future research directions, future funding applications, future research ideas and projects, and future collaborative opportunities. For example, knowledge gained in relation to specific peptides with utility for targeted delivery of oligonucleotides will provide insight into understanding of mechanisms (leading to future improvements), utility for application to other diseases (e.g. other neurological diseases) and to delivery of other drug cargoes (e.g. therapeutic siRNAs, miRNAs). Such specific knowledge and similar gains in project knowledge will not be restricted to the PI and Co-Is although these groups are likely to benefit soonest. Longer-term, success in numerous aspects of this project will provide fundamental knowledge in relation to the treatment of neurological disorders and will likely lead directly and indirectly to numerous long term academic beneficiaries building on and exploiting this knowledge in relation to other common and rare neurodegenerative diseases in particular and neurological diseases more generally.

NON-ACADEMIC BENEFICIARIES especially SMA patients will benefit directly from an advanced peptide SSO therapy, which could offer highly effective disease modification and improved quality of life to ALL SMA patients. SMA families will benefit immediately because such research is crucial to maintaining the morale of the SMA community. In the medium term, families of ALL SMA patients will benefit directly from a therapeutic agent (i.e. a product) that can be tested on their children offering the prospect of disease modification. Finally, non-academic beneficiaries in the commercial biotech/pharma sector are likely to benefit in the medium term through opportunities to acquire licences to intellectual property in relation to aspects of the technology - either specifically in relation to clinical development of the lead compound for SMA or more generally in relation to platform peptide and/or oligonucleotide technology that could have broader application. This is likely to lead to further development, a range of possible products and a range of possible commercial benefits for companies in the biotechnology or pharmaceutical sectors and/or investors in relation to such companies.


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