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Gene-based therapeutics – the face of next generation medicine

Gene-based therapeutics – the face of next generation medicine

Feb 16, 2011

Stated simply, gene therapy is an experimental technique that replaces, inactivates, or introduces a gene in the body to treat disease. Advances in the design of safer viral vectors, nano-particle based drug delivery and non-viral vectors have created a renewed interest in personalized medicine and gene therapy. Increased and predictable targeting precision is now possible. Some areas that can benefit from gene based solutions and novel drug delivery techniques include cancer, congestive heart failure, vaccines, HIV-AIDS and single gene inherited defects. The economic challenges associated with the treatment of chronic disease and the potential for lasting cures through gene therapy has led to resurgence in entrepreneurial effort in this sector. Here, we examine the scientific underpinnings, current entrepreneurial efforts, investment and regulatory environment and future direction for gene therapy.   

Gene Therapy Research  

An attractive feature of research in gene therapy is its inherently multi-disciplinary nature. While genetic insights and cellular mechanisms remain fundamental, the practicability and commercial viability of solutions depends on bio-engineering successes (e.g. liposomes, dendrimers, electroporation), newer viral gene delivery methods and bioinformatics approaches (sequencing and pattern matching, among others). A few notable successes have demonstrated the potential unleashed through successful integration of basic research and technology development. High-throughput screening, for instance, has helped identify several useful drug candidates and genetic targets of disease with higher precision in significantly less time and 4 fold reductions in processing cost as compared to conventional methods. However, functional knowledge gaps still remain, as only 2930 of the 13246 human genes with known sequences have been associated with a phenotype description and molecular basis.

State of Entrepreneurship in Gene Therapy

Let us look at some benchmarks. Zinc Finger Nuclease (ZFN) based approaches have been in the spotlight in recent years for the ease of manipulation and their specificity and reproducibility in targeting genome(s). Sangamo Biosciences recently demonstrated a ZFN based strategy to modify genetic defects for single gene and rare diseases [1]. Their aim was to permanently correct the dysfunction of the human gene F9 in a mouse model. Gene F9 affects clotting Factor IX as its downstream target, which has important implications for Hemophilia B. The study was collaboration between scientists at Sangamo and University of Pennsylvania. Another example is Congestive Heart Failure, the cause of 300, 000 deaths annually in the US alone (NIH/NHLBI statistics). The molecular mechanism is believed to be an insufficient level of cyclic AMP and has been tracked to abnormal function of the AC6 gene. One group working on gene therapy for this problem is Renova Therapeutics [2],  a company in San Diego, in collaboration with the VA San Diego Healthcare System and the William Beaumont Hospital in Michigan. The Renova group is conducting AC6 gene therapy treatments in CHF.  In their preclinical study, mice with cardiomyopathy (a type of Congestive Heart Failure) showed increased heart function and lived as long as normal, healthy mice when AC6 was increased.  In pigs, the AC6 gene therapy led to substantial improvements in heart function and reduced dilation of the heart.  Based on the result of these experiments, a clinical gene therapy trial was approved and initiated for human patients with severe heart failure. 

Bluebird Bio (formerly Genetix) [3], a Cambridge, MA based firm, has an array of genetic solution candidates for Childhood Cerebral Adrenoleukodystrophy (CCALD) and Beta-Thalassemia/Sickle Cell Anemia. Bluebird bio’s LentiGlobin® introduces a fully functional human beta-globin gene, under the control of the beta-globin promoter and locus control regions, into the patient’s own hematopoietic stem cells. Bluebird bio is conducting a Phase 1/2 trial examining the feasibility, safety and efficacy of LentiGlobin in the treatment of beta-thalassemia and sickle cell anemia. If successful, LentiGlobin therapy may avoid the mortality and morbidity associated with graft-versus-host disease and immune suppression and may eliminate the need for monthly transfusions and daily overnight intravenous iron chelation therapy to fight the dangerous overload of iron caused by chronic transfusions. To date, more than 1000 clinical trials for gene therapy solutions have been approved in the US alone; 57 of those are currently in Phase III and 2 are in Phase IV trials. Federal support is forthcoming as well; the U.S. National Institutes of Health is leading collaborative projects involving scientific, clinical and medical stakeholders. The NIH has earmarked about $275 million in funding for gene therapy-based approaches to drug development [4].

Investors and Regulators

For a long time, gene therapy was disfavored among investors because of the difficulty associated with delivering genes to target organs and the potential for a severe adverse reaction. Investors and researchers alike found themselves questioning the approach after a healthy teenager, Jesse Gelsinger, died of toxic shock in September 1999 after receiving the adenovirus vector carrying a potentially therapeutics transgene for the inherited condition Ornithine Transcarbamylase Deficiency as part of a volunteer clinical trial.

Improved safety through new techniques for gene delivery (outlined above) and new chemical gene carriers, which pose much less risk for such reactions, have, however, spurred a turnaround for gene therapy investment and research. Bluebird Bio [5], mentioned earlier, is a stellar example of this trend. The Company was able to raise over $35 million in venture financing (led by Third Rock Ventures), highlighting the change in investor perception. The FDA has also generated new stringent guidelines to address safety concerns. These FDA guidelines spell out the safety, purity and potency requirements for Cellular and Gene Therapy Products. One of the key issues is stability because most of these therapeutic molecules are proteins and thus subject to degradation over time and necessitating strict expiration dating and handling procedures for each proprietary product. All tissue-derived products also need to fulfill Current Good Tissue Practices, in addition to regular compliance and regulatory checks. Another salient concern with all gene therapy viral vectors is the potential for infection and in rare cases, carcinogenesis. This makes the approval process particularly arduous for these drugs.

The Future of Gene Therapy

Despite these recent successes, some challenges plague the full realization of gene therapy; short term versus long term results, immune response to viral vectors, chance of mutagenesis and multi-gene disorders are complex and grey areas. However, these gaps should be viewed as the template for important R&D opportunities rather than immovable roadblocks. While drug related adverse events and inconsistent outcomes can complicate clinical trial design, the potential benefits of genetic approaches are too great to ignore.  Furthermore, we desperately need new approaches to these target diseases as conventional treatment can be invasive, incapacitating and time consuming — degrading the quality of life for patients while offering only the slim possibility of a positive outcome. Indeed, we stand at a very interesting juncture where renewed interest in gene therapy is just one of the many inevitable changes in the treatment and management of human disease.



1 http://investor.sangamo.com/releasedetail.cfm?ReleaseID=535403

2 http://renovatherapeutics.com/

3 http://www.bluebirdbio.com/product-overview.php

4 http://report.nih.gov/rcdc/categories/

5 http://bostonbiotechwatch.com/2010/03/12/genetix-pharmaceuticals-a-gene-therapy-company-takes-down-35-million-in-a-compelling-turnaround-story/

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