ADENOVIRUS AS A VECTOR IN GENE THERAPY AND VACCINES
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ADENOVIRUS AS A VECTOR IN GENE THERAPY AND
VACCINES
http://www.virology.net/Big_Virology/EM/Adeno-FD.jpg
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STRUCTURE
Size: 70-90nmNon-enveloped icosahedral virus Capsid comprised of 3 surface coat proteins
FibersPentonsHexons
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Replication Cycle1) Absorption and Penetration
Bind to cell surface receptor Enters cell by endocytosis
2) Transcription Early transcription- Codes for non-structural, regulatory proteins Late transcription- Codes for replication substrates and
machinery3) Assembly4) Exit- Cell lysis
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NORMAL VIRAL TRANSMISSION
Airborne&
Waterborne
Transmission Routes: Direct and Indirect ContactHand-eye ContactFecal/Oral ContactVenereal ContactRespiratory Droplet Transmittance
*Incubation period of 2-9 days
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www.stanford.edu/group/virus/adeno/2005/
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ADENOVIRUS USE IN GENE THERAPY
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WHY ADENOVIRUSES ARE GOOD VECTORS FOR GENE THERAPY
IN CANCER PATIENTS Gene therapy works by manipulating viruses to contain “good genes” in which they can transport to the cells to code for needed protein/hormone/enzyme/etcThey do not incorporate their genes into the host genome. The Adenovirus is ubiquitous- it has been isolated from a large number of different species with over 100 known serotypesCan rapidly infect a large range of human cellsLow pathogenicity in humansCan hold large segments of DNAGenome does not undergo rearrangement at high ratesDNA is easy to manipulate with current recombinant DNA techniques
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How this virus is used in cancer therapy
1) Mutagen compensation Replacement or inactivation of oncogenes
2) Molecular chemotherapy (Suicide) Also known as suicide of target tumor cells
3) Genetic immunopotentiation Modifies tumor or immune cells to amplify
immunological recognition of neoplastic cells
4) Genetic modulation of resistance/sensitivity Modify sensitivity or resistance of cells to
chemotherapy (Chemoprotection)5) Antiangiogenic gene therapy (tumor
suppressor) Targets the development of new vessels in
tumor tissue, inhibiting its growth
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PERCENTAGE OF THE TYPES OF GENE THERAPIES USED
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Cancer Trials with Adenoviral Vectors
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ADENOVIRUS USE AS A VECTOR IN VACCINES
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Using a Human Adenovirus Vector in Vaccination
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ADENOVIRUS VACCINE USE IN HUMANS
Human Adenovirus Serotypes*Over 100 Known Serotypes!Most Common:HA-vd4HA-vd 7
DiagnosisRespiratory Tract Infection
Common cold symptomsSore ThroatSevere coughSwollen lymph nodesHeadacheNon-productive “croupy” cough
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Diagnosis cont.Intestinal Tract Infection
Abrupt onset of water diarrheaFeverAbdominal TendernessVomiting
•Notice: Both cases have very similar symptoms to common cold and influenza
• Respiratory secretion culture• Stool culture• Chest x-ray• Blood work
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ADENOVIRUS VACCINE USE IN TRACHEOBRONCHITIS
“KENNEL COUGH”CA-v1: causes Infectious Canine Hepatitis
*CA-v2: causes Infectious Tracheobronchitis
Canine Distemper-Adenovirus Type 2-Measles-Parainfluenza Vaccine is a Modified Live Vaccine
Freeze-Dried and stored at 2-7°C
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FUTURE WORK USING ADENOVIRUS AS A VECTOR
The majority of clinical trials done using the adenovirus in gene therapy have been phase 1
Phase 1 trials are used to determine safety, feasibility, and toxicity of the process
The Phase 1 trials have set the stage for future work with the next generation of Adeno vectors that will show less stimulation of the host immune system and can be selectively targeted to specific tissues. (Future Work in Vaccines)
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REFERENCESBaurschmitz G.J., Barker S.D., Hemminki A.
Adenoviral Gene Therapy for Cancer – from Vectors to Targeted and Replication Competent Agents. International Journal of Oncology. 2002.
McCormick F. Cancer Gene Therapy: Fringe or Cutting Edge? 2001. Nature Reviews Cancer. 1:1:2: pg 130-142.
Vorburger S.A., Hunt K.K. Adenoviral Gene Therapy. Oncologist. 2002. 7: 46-59.
Wagner E., Hewlett M.J., Bloom D.C., Camerini D. 2008. Basic Virology. Blackwell Publishing., M.A. 452 pp.
Akusjärvi G, Pettersson U, Roberts RJ: Structure and function of the adenovirus-2 genome. In Doerfler W (ed): Adenovirus DNA. Martinus Nijhoff, Boston, 1986.
Fields. Virology, 3rd edition. . Lippincott-Raven: Philadelphia, 1996. pp.2111-2171.
Gray, G.C. Adenovirus Transmission-Worthy of our Attention. J Infect Dis. 194: 871-873, 2006-editorial.