Gene therapy has become a clinical reality.
Adeno-associated virus (AAV) vectors are safe and efficient gene transfer tools based on naturally occurring non-pathogenic AAVs. AAV-based vectors have been extensively evaluated in preclinical and clinical studies and are increasingly used in the treatment of previously incurable diseases. These vectors have proven to be safe and efficient for the long-term expression of supplemented transgenes. Nevertheless, a broader use of AAVs in gene therapy is currently hampered by two important factors:
1) The limited DNA uptake capacity, which precludes the treatment of large genes
2) The limited ability to cross biological barriers, which demands local delivery and restricts the route of administration.

At ViGeneron we have developed three next-generation gene therapy platforms designed to overcome the above-mentioned limitations of existing AAV-based gene therapies.

ViGeneron’s pipeline is built on our novel and proprietary AAV technology platforms and addresses ophthalmic diseases with high unmet medical need.

Novel AAV Technology Platforms

vgAAV vector platform

vgAAV, ViGeneron’s proprietary AAV Vector platform, is our next generation vector platform based on novel engineered AAV capsids

In a unique in vivo directed-evolution approach we generated our vgAAV vectors. The vgAAV vector platform enables a superior transduction of target cells and is designed to efficiently cross biological barriers. These attributes allow vgAAV vectors to target a broad spectrum of cell types in the retina, thus enabling intravitreal, less invasive treatment administration. vgAAV’s capability to cross biological barriers makes vgAAVs also attractive tools for applications beyond ophthalmology.
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vgAAV, the novel and proprietary technology platform.

  • Unique: vgAAVs are uniquely engineered AAV capsids with novel properties
  • Proprietary: the vgAAV technology is fully owned by ViGeneron
  • Efficient: vgAAVs efficiently transduce target cells
  • Enabling: vgAAVs overcome biological barriers and enable novel, less invasive routes of administration
  • Easy to produce: vgAAVs are easily produced in high yields
  • Broadly applicable: vgAAVs are used for ophthalmology programs and have the potential to be applied to other serotypes and tissues, such as the central nervous and the cardio-metabolic system.

REVeRT vector platform

REVeRT, Reconstitution via mRNA trans-splicing, is our next generation vector platform for transfer of large genes

Messenger RNA (mRNA) splicing is a very efficient cellular process for the seamless ligation of adjacent protein coding sequences, thereby enabling the formation of a functional gene product. The splicing process, which normally takes place on a single pre-mRNA molecule (cis-splicing), can also be used to ligate two separate mRNA molecules. The latter is referred to as mRNA trans-splicing and is the basis of ViGeneron’s REVeRT technology.
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REVeRT was developed  to overcome the limited genome capacity of AAVs (<5Kb).
This technology offers a breakthrough in gene size limitations using dual AAV vector approaches. REVeRT enables highly efficient and precise reconstitution of two mRNAs encoding the proximal and distal portions of a large protein of interest. The split gene parts are packaged into individual vgAAV vectors, mixed, and co-delivered to the target tissue. REVeRT achieves high reconstitution efficiency at mRNA and protein levels.

REVeRT is a novel tool for the efficient delivery of large genes

  • Unique: REVeRT is the dual AAV vector technology working at the mRNA level
  • Proprietary: REVeRT technology is fully owned by ViGeneron
  • Efficient: REVeRT utilizes the highly efficient cellular splicing machinery
  • Specific: REVeRT generates the desired full-length protein with high precision
  • Seamless: REVeRT results in seamless ligation of sequences
  • Broadly applicable: REVeRT can be used with any serotype and in any disease indication

Transactivation platform

With our innovative AAV Transactivation platform, we unlocked the capability for bi-directional control over numerous endogenous genes. Leveraging our REVeRT platform, we orchestrate delivery of CRISPR/Cas in conjunction with single guide RNAs, which precisely targets Cas to the promoters of interest. The lengths of the single guide RNAs determine whether a gene undergoes upregulation or knockout.

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Applicable to haploinsufficiency and to all other hereditary diseases caused by mutations in genes for which functional equivalents exist: mutation- and gene size-independent.

Transactivation can be used to treat genetic diseases with autosomal dominant inheritance, for which gene supplementation needs to be combined with simultaneous knockout.

Transactivation can also be used to target more complex diseases, such as diseases caused by mutations in multiple genes, and enabling creative approaches for the treatment of non-hereditary diseases.

  • Versatile: Enables gene activation independent of gene size, and coregulating multiple genes at once
  • Specific: Uses sgRNA to specifically regulate the targeted genes only
  • Comprehensive: Drives expression of all physiologic isoforms
  • Physiologic: Maintains physiologic regulation e.g., based on intronic regulatory elements
  • Efficient: Achieves robust expression to improve functional outcomes

Scientific References

An overview of the most important papers about our innovative solutions published by our team.

1. Koch S, Sothilingam V, Garcia Garrido M, Tanimoto N, Becirovic E, Koch F, Seide C, Beck S, Seeliger M, Biel M, Mühlfriedel R, Michalakis S.  Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. Hum Mol Genet. 2012;21(20):4486-96 – more

2.  Riedmayr LM, Böhm S, Biel M, Becirovic E.  Enigmatic rhodopsin mutation creates an exceptionally strong splice acceptor site. Hum Mol Genet. 2019;29:295-304. doi: 10.1093/hmg/ddz291 – more

3.  Fischer MD, Michalakis S, Wilhelm B, Zobor D, Muehlfriedel R, Kohl S, Weisschuh N, Ochakovski GA, Klein R, Schoen C, Sothilingam V, Garcia-Garrido M, Kuehlewein L, Kahle N, Werner A, Dauletbekov D, Paquet-Durand F, Tsang S, Martus P, Peters T, Seeliger M, Bartz-Schmidt KU, Ueffing M, Zrenner E, Biel M, Wissinger B.  Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol. 2020;doi: 10.1001/jamaophthalmol.2020.1032. [Epub ahead of print] – more

4.  Böhm S, Splith V, Riedmayr LM, Rötzer RD, Gasparoni G, Nordsröm KJV, Wagner J, Hinrichsmeyer KS, Walter J, Wahl-Schott C, Fenske S, Biel M, Michalakis S, Becirovic E.  A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation. Science Advances 2020;vol. 6, no. 34, eaba5614 doi: 10.1126/sciadv.aba5614 –  more

5.  Panagiotopoulos AL, Karguth N, Pavlou M, Böhm S, Gasparoni G, Walter J, Graf A, Blum H, Biel M, Riedmayr LM, Becirovic E. Antisense Oligonucleotide- and CRISPR-Cas9-Mediated Rescue of mRNA Splicing for a Deep Intronic CLRN1 Mutation. Mol Ther Nucleic Acids 2020;21:1050-106 – more

6. Pavlou M, Schön C, Occelli LM, Rossi A, Meumann N, Boyd RF, Bartoe JT, Siedlecki J, Gerhardt MJ, Babutzka S, Bogedein J, Wagner JE, Priglinger SG, Biel M, Petersen-Jones SM, Büning H, Michalakis S. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders. EMBO Mol Med 2021 :e13392. doi: 10.15252/emmm.202013392. Epub ahead of print. PMID: 33616280 – more

7. Lisa M. Riedmayr, Klara S. Hinrichsmeyer, Nina Karguth, Sybille Böhm, Victoria Splith, Stylianos Michalakis & Elvir Becirovic; dCas9-VPR-mediated transcriptional activation of functionally equivalent genes for gene therapy; Nature Protocols 2022. volume 17, 781–818. PMID: 35132255 DOI: 10.1038/s41596-021-00666-3 – more

8. Manuela Völkner, Marina Pavlou, Hildegard Büning, Stylianos Michalakis, Mike O Karl; Optimized Adeno-Associated Virus Vectors for Efficient Transduction of Human Retinal Organoids ; Hum Gene Therapy. 2021 Jul;32(13-14):694-706. doi: 10.1089/hum.2020.321. Epub 2021 Jun 29. 7PMID: 33752467 – more