RNA Biology

What is RNA therapy? 

RNA therapy utilizes interfering RNA (RNAi) molecules to treat disease by regulating aberrant gene expression. RNA was once thought to be a mere byproduct of gene processing, but is now identified as a key component of gene regulation. Both endogenous and synthetic interfering RNA molecules have been found to change gene expression and ultimately, gene product levels.  Based on this discovery UMass created the RNA Therapeutics Institute, a center dedicated to the development of RNAi therapeutics. Over 25 novel RNAi technologies have been developed at UMass.  Importantly these RNAi therapeutics display improved target specificity thereby enabling optimal therapeutic efficacy.  Browse our technologies below.

RNA Therapy Invention Pipeline Table

 

Browse Our RNA Therapy Inventions:

 

2016

 

Title: Use of miR-122 to Treat Liver Diseases. UMMS16-56; Patent Pending.  

Title: Branched Oligonucleotides as Therapeutics. UMMS16-45; Patent Pending. 

  • This technology is based on the discovery that branched oligonucleotide structure improves the level of tissue retention in brain by more than 100 fold compared to non-branched compounds of identical chemical composition. The invention discloses branched oligonucleotides, specifically di-branched assymetric fully modified siRNAs, exhibiting great uniform distribution throughout the CNS and other target tissues, enhanced cellular uptake, minimal immune response and off-target effects, without formulation.

Title: A Process for Delivering Small RNAs to Sperm. UMMS16-37; Patent Pending. 

  • This invention provides methods to modulate transgenerational epigenetic inheritance, wherein some epigenetic phenotypes are maintained through generations. The disclosed method involves using epididymosomes, small vesicles found in the testis, to deliver RNA molecules to sperm, enabling tailored RNA delivery to the zygote upon fertilization. 

Title: A New Generation of Antihelminthic Medications that Trigger Aberrant Immune Responses in Pathogenic Nematodes. UMMS16-25; Patent Pending. 

  • The present invention is related to the treatment and prevention of nematode infection in mammals. In general, the present invention provides small organic compounds and RNAi molecules targeting the p38 mitogen activated protein kinase pathway in xenobiotic-resistant nematodes. Further, the present invention combines an immunostimulatory small molecule with a pharmacologic inducer of an endoplasmic reticulum unfolded protein response to provide a synergistic therapy for human pathogenic nematode infection. 

Title: Development of Anti-angiogenic miRNA Therapeutics for Corneal Neovascularization. UMMS16-23; Patent Pending. 

  • This new technology includes two novel inventions: 1) discovery of miRNAs that influences the neovascularization of the cornea and 2) optimization of rAAV gene therapy method for specific delivery to the cornea. Neovascularization is the most common corneal pathological condition and underestimated cause of blindness. Injection of the rAAV constructs that include synthetic nucleic acids that mimic or inhibit the discovered miRNA can reduce corneal neovascularization in mice.

Title: Novel Metabolically Stable Oligonucleotide Conjugates. UMMS16-09; Patent Pending. 

  • The invention discloses novel hydrophobically-conjugated oligonucleotides useful for RNA interference. The oligonucleotide conjugates are characterized by efficient RISC entry, minimum immune response and off-target effects, efficient cellular uptake without formulation, and efficient and specific tissue distribution.

Title: Identification of Epigenetic Modifiers of the Silenced FMR1 Gene: Potential Targets for Fragile X Syndrome Therapeutics. UMMS16-03; Patent Pending. 

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2015

 

Title: New XCI Inhibitors as Potential Rett Syndrome Therapeutics. UMMS15-53; Patent Pending.

Title: Developing of Soluble FLT1 Targeting Therapeutics for Treatment of Preeclampsia. UMMS15-50; Patent Pending. 

  • Selective elimination (filtration) of circulation "soluble fms-like tyrosine kinase 1" proteins (sFLT1s) in women with preeclampsia is a successful strategy for treatment of preeclampsia. The invention comprises oligonucleotide compounds that bind intronic regions of mRNA encoding sFLT1 protein, thereby inhibiting expression of sFLT1 protein for treatment of preeclampsia and other angiogenic disorders. Targeting these regions with RNAi compounds enables selective silencing of truncated, soluble variants without interfering with regular FLT1 function. Further, there is no detectable transfer of the oligonucleotides to the fetus.

Title: Development of Efficient and Safe rAAV Compatible Silencing Construct. UMMS 15-29; Patent Pending. 

  • This invention spans from the invention of UMMS15-28, an rAAV optimized for compatibility and efficacy for shRNA delivery. This process was tested in UMMS15-28 by examining the regional importance of shRNA within the viral genome. This upgraded shRNA-rAAV delivery system has optimized flanking sequences and shRNA structure. The shRNA backbone has lower loop complementarity, causing lower thermodynamic stability that increases its efficacy. This concept was tested by designing multiple Artificial miRNA (AmiRNA), where AmiRNA have the optimized structure while still possessing the shRNA interfering properties. This mechanism for shRNA deliver is highly efficient and safe for sustained silencing.

Title: Fully Stabilized Assimetric siRNA Compounds: an Optimal Scaffold for Conjugate Mediated Delivery. UMMS15-25; Patent Pending. 

  • This invention discloses hydrophobically-modified siRNA, featuring an advanced stabilization pattern, "hsiRNA-ASP". These siRNA compounds having the following properties: (1) fully chemically stabilized (i.e., no unmodified 2'-OH residues); (2) asymmetry; (3) 11-16 base pair duplexes; (4) alternating patten of chemicically-modified nucleotides (e.g., 2'-flour and 2'-methoxy modifications); (5) single-stranded, fully phosphorothioated tails of 5-8 bases. siRNAs with these structural properties show a dramatic enhancement in potency (5-10) fold in unassisted delivery. Also embodied are hsiRNA-ASPs conjugated to targeting agents including, but not limited to, cholesterol. Further, alteration of hsiRNA-ASP PS content has a major impact on tissue distribution and oligonucleotide uptake making these compounds very attractive therapeutic agents.

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2014

 

Title: Position specific requirements for nucleotide pairing or mismatches between microRNA or small interfering RNA (siRNA) and target RNA to promote occupancy and retention of an Argonaute protein or RNA-induced Silencing Complex (RISC) on a target RNA. UMMS14-70; Patent Pending.

  • This new invention of “tether” oligo allows for siRNA delivery with higher potency and tissue specificity in medical applications. Tethering endogenous miRNAs that are highly tissue specific can direct them to the target mRNA of interest and this nuclease-resistant oligo can robustly increase efficacy of siRNA therapy. Unlike previous methods, this oligo restricts siRNA to specific cell types which may yield reduced off-target effects.

Title: Oligonucleotide Compounds for Targeting Huntingtin Gene. UMMS14-51; Patent Pending. 

  • This new invention spans from the discovery of potent silencing site that was previously unidentified on Huntington gene (htt) through screening of more than 200 compounds. Conventional siRNAs will target this 3’ UTR site for potent inhibition.  Efficacy was demonstrated using different siRNA configurations in several cell types and primary neurons that may aid research and future therapeutic applications.

Title: Efficient Exosomal Loading Using Hydrophobically Modified Therapeutic Oligonucleotides. UMMS14-09; Patent Pending.

  • This novel invention discloses a novel RNAi delivery vehicle. Specifically, describing methods of loading exosomes with hydrophobically modified nucleic acids which exhibit a much higher loading efficiency than methods currently used (i.e. electroporation, transfection with cationic lipid reagents, and ultracentrifugation).

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2013

 

Title: COMPOSITIONS AND METHODS FOR CHARACTERIZING AND TREATING MUSCULAR DYSTROPHY. UMMS13-53; Patent 9,260,755

  • This invention provides a patented chimeric mouse model for Facioscapulohumeral muscular dystrophy (FSHD) that can be used to further characterize the disease or identify potential therapeutic agents. In a related pending patent application, the invention further discloses inhibitory nucleic acids targeting one or more of SLC34A2, TRIM49, TRIM43, CD177, NAAA, HSPA6, TC2N, or CD34 to treat FSHD.

Title: Selective, siRNA-Mediated Knockdown of CB1 Receptors in Macrophages for the Treatment of Diabetes. UMMS13-52; Patent Pending.

  • Novel compositions and methods for the treatment of type 2 diabetes mellitus using glucagon-encapsulated siRNA directed against human cannabinoid receptor 1 (CB1). The glucan-encapsulated siRNA's specifically target phagocytic macrophages upon administration.

Title: MicroRNA Mediated Knockdown of SOD1 Using Recombinant Adeno-associated Vectors. UMMS13-19; Patent Pending. 

  • This invention discloses a novel miRNA delivered by rAAV for silencing SOD1 & C9orf72 SODl genes, which are associated with ALS. This method enables effective therapy at low doses with the persistence of rAAV episomes that continually expresses the nucleic acids, thus rendering re-treatment unnecessary. This method also minimizes rAAV exposure to non-CNS peripheral tissue.

Title: Peptide-modified Glucagon Particles for Delivery of Therapeutic Cargoes. UMMS13-05; Patent Pending. 

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2012

 

Title: Purification of Small RNAs from Human Biofluids. UMMS12-57; Patent Pending. 

  • This invention provides methods for isolating circulating small RNAs from plasma/urine, CSF, or tissue samples, the method comprising using an alkaline phenol:chloroform extraction, and methods of use thereof, including for the detection, prognosis, and/or monitoring of disease in a subject. These methods significantly increase the yield of many assayable small RNAs such as miRNA, some by tenfold or more over present standard methods.

Title: COMPOSITIONSANDMETHODSFOR DECREASING LEUKOCYTE EXTRAVASATION AND VESSEL FLUID LEAKAGE. UMMS12-52; 9,434,951. 

  • The technology provides novels compositions and methods for preventing formation of atherosclerotic plaques by administering inhibitory oligonucleotides, e.g. miRNA, that decrease Mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4).  This invention is based on the discovery that oligonucleotides that decrease the expression of Map4k4 mRNA in an endothelial cell reduce the induction of leukocyte adhesion molecules and reduce endothelial cell monolayer permeability.  Further provided are methods of using oligonucleotides targeting Map4k4 therapeutic agents for atherosclerosis.

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2011

 

Title: Uses of SARM for the Treatment of Neurodegenerative Disease and Neural Injury. UMMS11-10; Patent Pending. 

  • This novel patented technology provides methods of treating peripheral neuropathy, brain injury, and neurodegenerative disease utilizing an siRNA that inhibits sterile a/ Armadillo/To 11-Interleukin receptor homology domain protein (SARM) expression. This invention is based on the discovery that inhibition of SARM mRNA reduces axonal and synaptic degeneration in mice. The invention further provides methods of identifying potential therapeutic agents that modulate SARM.

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2010

 

Title: Characterization of Positioning Effect of POL III-SHRNA Transcription Unit in SCAAV Vector Genome on the Packaging Efficiency and Functionality of SHRNA Silencing. UMMS10-40; Patent Pening. 

  • Newly designed multicistronic expression construct with efficient shRNA delivery. Hairpin RNAi expression cassette shown to specifically improve replication and packaging efficiency.

Title: AAV-BASED TREATMENT OF CHOLESTEROL-RELATED DISORDERS. UMMS10-37; Patent 9,272,053

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2009

 

Title: AAV’S AND USES THEREOF. UMMS09-58; Patent  8,734,8099,284,357

  • Novel AAVs with tissue targeting capability for application in therapeutic gene therapy and research purposes. With efficient delivery, these AAVs have minimal toxic effects on local tissues. They can also be used to develop somatic transgenic animals with a tissue specific promoter. Additionally, this invention includes composition and a method for isolating other novel AAVs. This technology can be used to express RNAi or RNAi sponge that inhibits one or more RNAi functions in a tissue.

Title: Identification of Genes Preferentially Required for Growth of p53-Deficient Human Cancer Cells. UMMS09-56; Patent Pending. 

  • This invention discloses a novel cluster of genes discovered through a RNAi screen which could be a potential target of cancer treatment in p53 mutation cancers. p53 gene is mutated in numerous cancer therefore the newly discovered genes have potential for becoming a therapeutic target in wide range of cancers. The inventors performed a bias screen using p53 mutant cancer cells, p53-/- and +/- colorectal HCT116 cell lines and shRNA library. This screening yielded a selection of genes that are preferentially required for viability in p53 mutant cancer cells.  The verification experiments showed that a 24 gene-knockdown preferentially impaired growth of the p53 cell line. Using mice xenograft, 4 required genes were identified and show high potential for clinical use.

Title: MODULATION OF HUMANCYTOMEGALOVIRUS REPLICATION BY MICRO-RNA 132 (MIR132), MICRO-RNA 145 (MI145) AND MICRO-RNA 212 (MIR212). UMMS09-35; Patent 8,933,0459,562,232

  • This patented invention provides methods of attenuating HCMV replication by modulating miR145 and targets thereof. Also provided are methods of detecting an HCMV infection, and compositions and kits useful for attenuating HCMV replication.

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2008

 

Title: ISOLATION OF NOVEL AAVS AND USES THEREOF. UMMS08-55; Patent 9,217,155

  • The technology utilizes methods of implementing viral vectors harboring a transgene(s) in combination with tissue specific anti-miRNA sequences to minimize off-target effects. In addition, this method allows for production of somatic transgenic animal models by targeted destruction of specific cell types. 

Title: ENCAPSULATED NANOPARTICLES FOR NUCLEIC ACID DELIVERY. UMMS08-09; Patent 8,389,485  

  • This invention discloses a new method for delivery of nucleic acids, including agents for gene silencing (e.g. siRNAs). This new system is developed with exterior of yeast cell wall particle (YCWP) and interior comprising multilayer nanoparticle core with a payload complex. Using this technology, inventors have effectively shown siRNA can be delivered effectively in macrophages. 

  

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