Leading RNA-Based Technologies
The advanced science behind our RNA-based discovery, research and development programs differentiates our technologies and the potential of our pipeline to provide transformative treatment options. Our core phosphorodiamidate morpholino oligomer (PMO) antisense technology is uniquely versatile, allowing for the development of a range of therapeutic candidates that target different types of RNA. Unlike most other RNA-based approaches, such as small interfering RNA (siRNA), Sarepta’s technology can directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate or up-regulate targeted genes or proteins (i.e. turn “on” or turn “off” production of a target protein).
We believe that the differentiated characteristics of our technology represent a significant improvement over traditional antisense drug utility and have the potential to greatly enhance clinical value over other RNA-based approaches. This diversity of application allows for the rapid design and development of novel therapeutic candidates, including candidates addressing previously difficult to target rare diseases.
Today, with several RNA therapeutic candidates in clinical and preclinical development, we are rapidly advancing our programs to provide patients with innovative and potentially transformative treatment options.
Phosphorodiamidate Morpholino Oligomers – PMOs
The linking of sequenced monomers with nucleic acid bases to create oligonucleotides is common to all RNA-based therapeutics. However, researchers can change the chemical character of the therapeutic molecules in subtle but significant ways. For example, the fine structure and charge of the monomers determines the strength of the linkages that hold them to their target. The backbone of the oligonucleotide can be altered to achieve different properties, such as bioavailability or resistance to enzymatic degradation. These and other differences in the characteristics of RNA-based therapeutics may alter the safety and efficacy profiles of different drug candidates, even if they are sequenced to target the same RNA.
Sarepta’s advanced RNA platform is based on our pioneering work with phosphorodiamidate morpholino oligomers, or PMOs. PMOs are synthetic structures modeled after the natural nucleic acid framework of RNA, but with critical structural modifications designed to allow for the functional manipulation of the molecules’ drug-like properties. The chemistry-based advantages built into our PMO technology address several pharmaceutical needs not consistently addressed by early generation antisense chemistries including stability, efficacy, specificity, delivery and safety. We describe our PMO compounds as “oligomers” rather than oligonucleotides due to their unique synthetic chemical structure.
PMO-based Core Chemistry
While PMOs have the same nucleic acid bases naturally found in RNA or DNA (i.e. adenine, cytosine, guanine, uracil or thymine), they are bound to morpholine rings instead of the ribose rings used by RNA. They are also linked through phosphorodiamidate rather than phosphodiester or phosphorothioate groups. This linkage modification eliminates ionization in the usual physiological pH range, so PMOs in organisms or cells are uncharged molecules. The entire backbone of a PMO is made from these modified subunits.
|Property||Traditional Antisense||siRNA||Sarepta’s PMO Chemistries|
Ability to target specific genetic sequences without risk of non-specific immunomodulation effects
Excellent safety profile preclinically and clinically up to high doses
|Distinct Mechanisms of Action:
Ability to modulate gene expression, including up-regulation of gene expression
Expanded flexibility allowing chemical modification for specific tissue and pathogen targeting
Resistant to enzymatic degradation in vivo
We believe these key differences provide our RNA therapeutic candidates with pharmaceutical properties that are preferable in order to achieve broader drug characteristics and greater potential clinical utility than the other antisense compounds.
Proprietary, Advanced Generation PMO-Based Chemistries
Sarepta has dedicated significant resources to the development of advanced generation RNA-based antisense chemistries with superior drug-like performance characteristics. This investment has been productive and we are currently applying several novel and proprietary PMO based platform chemistries to the discovery and development of new drug candidates. Specifically, we have advanced our foundational PMO chemistry through the construction of a series of novel and proprietary PMO-based platforms.
Sarepta’s most recent advance in chemistry, PMO-X, is focused on the incorporation of new proprietary chemical technology to fine-tune important physicochemical properties, intended to enhance in vivo tissue targeting, selectivity, and potency. The intrinsic neutral structure of the PMO provides continuing opportunities to create innovative and potentially transformative RNA-based therapeutics with varied beneficial properties.
Another proprietary analogue platform, our PMOplus™, uses the addition of positionally specific molecular charges into the PMO backbone. This is intended to specifically enhance drug performance characteristics on two key parameters: targeted cell penetration, and the maintenance of antiviral performance in the presence of viral mutation.
Sarepta has developed a proprietary technology of peptide conjugated phosphorodiamidate morpholino oligomers, or our PPMO platform. Using our PPMO technology, cellular uptake of the active PMOs, as well as their potency and specificity of tissue targeting, are significantly enhanced by the conjugation of arginine-rich cell-penetrating peptide chemical moieties (CPPs) to a PMO.
We are researching additional chemistry advances to further optimize our core proprietary technology platforms as well as to develop further novel analogues that we believe could provide beneficial characteristics, such as potency, bioavailability, therapeutic index and tissue selectivity, to our drug candidates.
Sarepta’s core technology is versatile, allowing for the development of a range of potential therapeutic compounds that target different types of RNA. Unlike most other RNA-based approaches, Sarepta’s technology has been used to directly target both messenger RNA (mRNA) and precursor messenger RNA (pre-mRNA) to either down-regulate or up-regulate targeted genes or proteins.
Splice Switching Oligomers (SSOs)
When designed to target pre–mRNA, which is not yet mature and needs to be processed and spliced to make mRNA, we refer to our compounds as Splice Switching Oligomers, or SSOs. Each gene in the genome can code information for the expression of multiple proteins via a process called alternative RNA splicing. Our PMO-based SSO technology enables manipulation of the alternative splicing process to direct protein expression and represents a relatively new and dynamic area of RNA–based drug discovery.
SSOs can direct alternative splicing by guiding the pre-mRNA cellular splicing machinery toward one of multiple alternative protein expression outcomes. The direction of alternative splicing via SSO may lead to a preference for a splicing variant naturally seen in nature, or an entirely novel alternative not a part of normal gene expression. In either case, the objective is to produce an important therapeutic outcome. Sarepta’s current SSO compounds in development include those targeting Duchenne muscular dystrophy.
Exon Skipping With SSOs
Genes stored in human DNA are organized in short DNA stretches, called exons, that code for fragments of the protein regulated by that gene. Exons are separated by long, non–coding pieces of DNA called introns. During processing of pre–mRNA, which is copied from the DNA template, introns are removed and exons are spliced together to create the mature mRNA. The mRNA thus brings the exons together, providing a contiguous set of instructions from which the full protein can be translated.
Our SSOs have the potential to manipulate splicing in a way that is distinct from conventional antisense or siRNA based approaches to modulate the alternative splicing process.
By targeting elements in precursor RNA that are essential for splicing, our SSO compounds force the cellular machinery to skip over targeted exons, creating an altered mRNA template. In a disease situation, SSOs are intended to prevent formation of harmful proteins and help restore beneficial proteins. When the exon contains a disease–causing mutation, for example, the resulting altered protein may have its function restored, partially restored or neutralized by forced skipping of a specific exon. This approach may be used to overcome the consequences of certain disease–causing mutations.
Therapeutic applications of SSOs include:
- Inhibition of mRNA production via a kinetically favored process
- Repair of RNA mutations
- Expression of novel proteins
- Alteration of protein compartmentalization
- Alteration of the profile of protein isoforms
Translation Suppressing Oligomers (TSOs)
When the target is mRNA, which translates genetic information into protein, Sarepta compounds are called Translation Suppressing Oligomers or TSOs. Sarepta’s current TSO compounds in development include, for example, those targeting hemorrhagic viruses.
TSOs are PMO based compounds that interfere with gene expression or other mRNA–dependent cellular processes by binding to their specific target sequence in mRNA. TSOs have high mRNA binding and act by a steric–blocking mechanism to inhibit protein translation, instead of by mRNA degradation mediated via RNAse H or RISC. We can use different PMO analogues as TSOs to achieve down regulation of genes or silencing of targeted mRNA sequences.
The primary application of TSOs is to inhibit the translation of either a specific endogenous or pathogenic agent protein through this binding process, thus inducing a desired therapeutic effect.