Second Generation Antibody Therapy
VIRxSYS has preliminary data that encourages further evaluation of the feasibility of utilizing its SMaRT™ technology to generate certain required antibodies in the human body, replacing the commercial manufacturing of antibodies which are injected into a patient.
The Company has performed some early work in applying the SMaRT™ technology platform to the generation of antibodies in vivo [1]. This would work as follows: VIRxSYS vectors would be engineered to have an affinity to a specific cell type (e.g. a liver cell). These cell-specific vectors would also be constructed to carry a certain PTM encoding for the therapeutic antibody RNA sequence of interest. The PTM selected would be one that can reprogram a specific and abundant gene transcript in the targeted cell. When VIRxSYS’ vector delivers the PTM to the cell, the specifically targeted gene transcripts in that cell would be re-programmed to produce the desired antibody protein. This antibody would be secreted into the plasma, migrate throughout the body, and perform its natural function. The potential patient benefit of this approach would be that the reprogramming process may be able to produce the desired antibody protein for up to 6 to 9 months, and possibly longer, compared to current antibody injections lasting only up to a dozen days or so.
This is an early stage project and could take several years before entering into human clinical trials. However, proof of principle has been demonstrated in mice, showing that the antibody molecule could be detected in the blood just eight hours following administration [1]. This approach of having the body manufacture antibodies in vivo would have many benefits including a lower manufacturing cost and a longer antibody impact in a patient.
Reference:
[1] Wang et al. Trans-splicing into highly abundant albumin transcripts for production of therapeutic proteins in vivo. Molecular Therapy 17:343-351, 2009 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835072/pdf/mt2008260a.pdf)
Stem Cell Applications
Stem cell applications hold great promise. VIRxSYS believes that our platform technologies of gene delivery (lentiviral vectors) and gene re-programming (SMaRT™) can make significant contributions to the research and development of therapies using adult stem cells to create pluripotent stem cells, specifically induced pluripotent stem (iPS) cells. Using iPS cells avoids the use of human embryos and the related ethical issues.
Our scientists are working with the Johns Hopkins University on these latest stem cell approaches, which involve the reprogramming of adult, mature and fully differentiated cells into pluripotent stem cells able to generate any human tissue or organ. We are very excited about the future potential of this collaboration. In addition, VIRxSYS has recently received a competitive grant from the State of Maryland to create safer and more efficient methods to generate iPS using the Company SMaRT™ and lentiviral vector technologies.
SMaRT™ Image (Molecular Imaging)
SMaRT™ Image can be used to perform real time molecular imaging of gene expression and has potential applications both in pre-clinical research and human diagnostics. SMaRT™ has the ability to trans-splice any reporter gene into any expressed gene transcripts that contains at least one intron to provide true real-time molecular imaging. Reporter genes that encode for fluorescent or luminescent proteins may be used for optical imaging while other reporter genes, such as thymidine kinase, make the technology adaptable to positron emission tomography (PET). In pre-clinical research, imaging can be applied in target validation, drug discovery or drug and vector distribution.
SMaRT™ Image has a significant advantage over conventional, direct imaging methods. Direct approaches traditionally use molecules such as antibodies that interact with the final gene product of interest: the protein. Screening for new antibodies specific to a particular protein is time consuming and increases the cost to develop new imaging reagents. However, SMaRT™ enables the rapid development of new imaging molecules. The PTMs used for molecular imaging have two standard coding sequences: (i) that of a fluorescent/luminescent protein or (ii) PET reporter. These PTMs differ only in their binding domains which are specific for each targeted gene transcript of interest. This modular nature enables rapid development of the PTM for a particular application.
There have been two publications on molecular imaging in top-tier medical journals, the Proceedings of the National Academy of Sciences USA [1] and the Journal of Nuclear Medicine [2]. In a commentary accompanying our article in the Journal of Nuclear Medicine¸ Dr. Ponomarev, a leading scientist in the field wrote, “This study represents an important step toward a universal imaging methodology of an endogenous mRNA target, with potential applications in research and diagnostics.” [3].
References:
[1] Bhaumik et al. Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing. PNAS 101:8693-8698, 2004 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423257/pdf/1018693.pdf)
[2] Walls et al. A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing. J Nucl Med. 49:1146-54, 2008 (http://jnm.snmjournals.org/cgi/reprint/49/7/1146.pdf)
[3] Ponomarev V. Imaging regulation of endogenous gene expression using spliceosome-mediated trans-splicing. J Nucl Med. 49:1035-7, 2008 (http://jnm.snmjournals.org/cgi/reprint/49/7/1035.pdf)