Using gene therapy to treat genetic diseases and cancers

Sometimes something as little as a chance encounter or as simple as reading a certain magazine can have life-altering consequences. Forty years ago such an event occurred in Dr. Arun Srivastava's life that altered the path of his career. As a first year graduate student at the Indian Institute of Science, Srivastava stumbled across a 1973 article in a scientific journal, Nature, by Dr. Thomas Cavalier-Smith of University of Oxford. In his article, Cavalier-Smith hypothesized how single-stranded DNA might replicate. Dr. Srivastava knew that a few years earlier, AAV (Adeno-associated virus), which contains a single-stranded DNA, as opposed to the typical double-stranded DNA, which is present in all cells, had already been discovered. This omittance struck a chord with Dr. Srivastava, who wrote to Dr. Kenneth  Berns, the preeminent scientist researching the virus at the time, a member of the National Academy of Sciences, and a potential Nobel Prize candidate, and began a career-long collaboration that would ultimately define Dr. Srivastava's career.

AAV, or Adeno-associated virus, is a virus that is known to infect nearly 90% of humans but that does not cause any disease and invokes very little immune response. This virus, which integrates into a single site into Chromosome 19 of the human DNA sequence, infects almost all cell types, without inducing any damage. This ability to efficiently invade human tissue and cells, yet not be attacked by the immune system, qualifies it as an ideal vector for gene therapy treatment procedures. Dr. Arun Srivastava of the University of Florida, has worked with this virus for nearly 4 decades, and is making significant strides in improving the deliverability and efficiency capabilities of the virus as a useful instrument in the delivery of gene-targeted therapy.

The improvement of AAV as a vector occurs in two stages:

  • The Next Generation AAV vectors, or "NextGen", undergo a modification of their capsid proteins (the protein shell of a virus) that increases nuclear delivery of viral genetic material into the host cell, greatly reducing effective dosage. Changing the capsid proteins results in the virus directly targeting the nucleus of cells, reducing the amount that is lost in the cytoplasm of the cell. Research also indicates this alteration makes the virus less immunogenic, or less likely to provoke immune-system response.

  • The Generation X AAV vectors, or "GenX", are being developed with the intention of improving vector efficiency, which will allow for highly-efficient transgene expression. This idea is based on the hypothesis that the removal of the binding site for the NF-kB repressing factor (which negatively impacts the transduction efficiency of single-stranded AAV vectors) together with the insertion of the full glucocortinoid receptor-binding element (GRE) will eliminate the naturally-occurring inhibitors that currently prevent full gene expression.

The ultimate goal of the research is to be able to safely combine the NextGen AAV and the GenX vectors into the optimized AAV (OptAAV) vectors. Dr. Srivastava has also identified two specific AAV serotypes, AAV3 and AAV6 vectors, which target respectively the human liver cells and human bone marrow stem cells extremely efficiently. AAV was approved by the FDA in 1996 for use as a vector, and while AAV is in use in a number of Phase I/II clinical trials, the high doses required lead to stronger host immune response, ultimately reversing any progress made by treatment. Dr. Srivastava summarizes the need to evolve from using 1st generation (natural) AAV vectors to those he is developing in five elegantly simple points:

  1. NextGen/GenX AAV vectors are highly efficient

  2. They are tissue-specific (target specific cells and organs in the body)

  3. They are stem-cell specific

  4. The advanced mutations enable lower doses to be used, which lowers both the production cost as well as the economic cost per patient

  5. There is evidence of efficacy in human cells using the NextGen/GenX AAV vectors ensuring translation into the clinic with higher probability of success

The ability to utilize the optimized AAV vector will allow for more effective gene therapy treatments. Two human diseases that have been identified for ideal AAV gene therapy are Hemoglobinopaathies (sickle-cell disease and beta-thalassemia) which are the most common group of genetic diseases affecting 1 in 600 humans worldwide, and liver cancer, which is the most common cancer in children and the third most common cause of cancer-related deaths in adults worldwide. Additionally, AAV has already been used as a vector for gene therapy treatments that have successfully cured a number of human diseases, such as lipoprotein lipase deficiency, hemophilia B, Parkinson's disease, alpha aromatic amino acid decarboxylase deficiency, and even  a form of blindness; 3 simultaneous trials saw over 30 patients, who had previously been unable to see for 15+ years, cured of their blindness. Gene therapy is easily one of the most promising medical treatments to be discovered in recent years, and the ability to successfully and efficiently deliver these treatments will greatly improve the odds for patients with many of these diseases.


Since deciding to specialize his research on AAV, Dr. Srivastava has collected nearly 35 years of research on the virus.

Dr. Srivastava's name is listed on five issued US patents, with applications filed for seven more:

  • U.S. Patent No. 5,252,479. Safe Vector for Gene Therapy

  • U.S. Patent No. 6,521,225. AAV Vectors

  • U.S. Patent No. 7,052,692. Role of Tyrosine Phosphorylation of a Cellular Protein in Adeno-Associated Virus 2-Mediated Transgene Expression

  • U.S. Patent No. 8,445,267. Tyrosine-Modified Recombinant Adeno-Associated Virus Vector Compositions and Methods of Use

  • U.S. Patent No. 8,492,344. Targeting the PDK2-DCA Binding Pocket for Novel Cancer Therapies

Over 50 scientific journals list Dr. Srivastava as a reviewer, including titles such as Blood Cancer Gene Therapy, Cancer Research, Current Gene Therapy, Gene Therapy, Human Gene Therapy, Irnational Journal of Cancer, Journal of Biological Chemistry, Journal of Clinical Investigations, Journal of Experimental Medicine, Journal of Virology, Molecular Cell, Molecular Therapy, Nature, Nature Biotechnology, Nature Cell Biology, Nature Communications, Nature Medicine, PLoS One, PLoS Pathogen, Proceedings of the National Academy of Sciences, USA, Science Translational Medicine, Stem Cells, and Virology.

Dr. Srivastava is also Executive Editor, Journal of Genetic Syndromes and Gene Therapy

Dr. Srivastava is also a Member of the Scientific Review Board, Gene Therapy Resource Program, National Institutes of Health


In the News

UF Pediatric Research, Arun Srivastava, Ph.D.

This is Dr. Srivastava's university website, providing basic biographical information as well as a general overview of research projects

Arun Srivastava, PhD

A university website providing a more detailed summary of Dr. Srivastava's research


NIH Grant

"Regenerative Medicine Training Grant" 2007-2011

St. Baldrick's Foundation (Fellowship)

"Development of Targeted therapy of infant leukemia"

Howard Hughes Medical Institute

University of Florida Science for Life for Undergraduate Student (Bart Kachniarz) 2007-2008