Glimmers of Hope - Part III

Profiles of Kennedy's Disease Researchers

In this post, I wish to recognize another researcher who is carrying the baton:

Parsa Kazemi-Esfarjani, B.Sc., Ph.D., is a researcher for the Department of Pediatrics, Division of Genetics, Institute for Genomic Medicine at the School of Medicine, University of California, San Diego.

Author's Note: This post is a little longer than normal, but I did not want to edit it to a point that Parsa's enthusiasm on the topic was lost.

Bruce: Why did you decide to focus your research on Kennedy's Disease?

Parsa: My entry into the Kennedy's Disease community was a great coincidence. In 1990, as a master's degree candidate, I was looking for a lab and a research program where I could learn the cutting edge techniques in molecular biology and genetics, and a program with a direct relevance to human disease.  I found all of that in Leonard Pinsky's lab at Lady Davis Institute, McGill University, in Montreal.

In Kennedy's disease, the repeat stretch consists of the amino acid glutamine, also called a polyglutamine).  As I was planning and designing experiments such as deleting the various repeat tracts, including the polyglutamine tract, and studying how they affected the function of the androgen receptor in cell cultures, I came across the report in the journal 'Nature' by Al La Spada and Kurt Fischbeck and their colleagues. Al's publication was a great impetus for me to ramp up my work and focus it on the notorious polyglutamines. Len Pinsky did warn me that the new discovery would generate a great deal of interest among scientists and a high level of competition, but I was young and daring and plunged right into the fray.

Even though I am presently not as youthful as I was then, I believe I am still daring! That is why over the past three years, I have concluded that the next frontier for Kennedy's Disease and other neurodegenerative disorders is the exploration for a safe and effective gene therapy system. We have plenty of therapeutic candidate genes, genetic drug targets, and other nucleic acid and protein derivatives, such as RNAi systems and neuroprotective peptides. It is time to put all of them to good use by properly delivering them to their intended targets.

Bruce: Briefly summarize what you are currently working on and why you feel it is important in KD research.

Parsa: As I mentioned above, my ultimate, long-term goal for the foreseeable future is to develop an effective and safe gene therapy so we could take advantage of the hundreds of candidate therapeutic genes that we have discovered over the past decade. These genes have been discovered through a remarkable international effort and at a high cost: 1) employing genetic screens in cell and animal disease models, such as yeast, worms, fruit flies; 2) using the new bioinformatic tools to compare the expression of thousands of genes at once in the disease and healthy tissues; and 3) adopting the candidate gene approaches in cell culture and animal models, examining the genes with suspected disease application based on prior knowledge.  However, the research grant proposal that I submitted to Kennedy's Disease Association also addresses a crucial aspect of gene and cell therapy: which cell populations or tissues contribute to the toxicity by the expanded-polyglutamine androgen receptor, and ultimately to Kennedy's disease? And, to what extent they do it?

Once we know the answer to these questions, we can redeploy our resources to develop the therapeutic agents and vectors for the appropriate cell and tissue targets.  In that way, we shall increase the probability of a positive clinical outcome in patients and simultaneously reduce the odds of seeing negative side effects.

 Bruce: What are your aspirations (career goals)?

Parsa: Based on the guerrilla tactics that are required to make leaps, as oppose to small incremental advances, in a complex field such as gene therapy for neurodegenerative disorders, I could not have asked for a more nurturing and positive environment than Al La Spada's lab and UCSD. As a research faculty, I would be able to devote my full attention to validating genetic and cellular therapeutic targets and collaborate with our colleagues to develop the long-sought systemic gene delivery for neurodegenerative disorders such as Kennedy's Disease.  Establishing effective gene therapy tools and strategies would open the doors to future combinatorial gene therapy to improve efficacy and safety by delivering multiple therapeutic genes at once, with each gene expressed at a much lower, less toxic, level, hence less side effects in patients. To continue my career in this line of effort, in time, I shall seek a well-funded position in an institute with a superb research infrastructure and outstanding colleagues and trainees with whom I can intellectually engage and collaborate.

 Bruce: You are a strong advocate of Gene Therapy. Would you care to comment on where we are at with this opportunity?

Parsa: With respect to the current state of gene delivery to the central nervous system, we are still fighting The Great War, flying biplanes and dropping 20-pound bombs on the enemy (i.e., poylgutamines, Abetas, prions, etc.).

With Al La Spada's support, one of my missions in our new theatre of research at UCSD is to mobilize a collaborative research project among the topnotch faculty at UCSD and its affiliates to develop a more advanced gene therapy system. The new vectors, a combination of viral and non-viral vector technology, could be administered intravenously (by injecting into veins as opposed to intracranially (through the skull) or intrathecally (through the spinal canal)) and the vector carrying the therapeutic genetic cargo would be distributed through the CNS via its microcapillaries and across the blood-brain barrier.

A tremendous amount of groundwork has already been done by diverse groups of researchers with the same enthusiasm about the prospects of gene therapy: geneticists, biochemists, chemists, molecular biologists, virologists, engineers, pathologists, etc. It is only a matter time and our determination to put all the available technology together to create clinically applicable gene delivery systems. In fact, there are several publications in the recent years that show success in systemic gene delivery in preclinical research.  (If you care to learn more about this, comment below and I will post the publications referenced)

 Bruce: Is there anything else you would like to mention?

Parsa: For most scientists, the human face of the medical research is the ultimate motivating factor. When experiments fail, funding is not granted, a manuscript is not accepted, or one simply yearns to leave the office or lab in the evening and join the family; thoughts of other families who depend on this research and its outcome, provides the mental fuel for those tougher extra miles.