FDA Regulation of Anti-Aging Gene Therapies

Lisa Carlson FDA Regulation of Anti-Aging Gene Therapies I. Introduction The quest for youth and immortality is not a novel pursuit in human history. Most notably, the goal of 16th century Spanish explorer, Ponce de Leon, was to find the fountain of youth and drink from its water to attain immortality.1 A literal fountain of youth is a fairytale notion. The prospects of gene therapy; however, are bringing the idea of eternal life closer to reality. Researchers around the world are attempting to slow or reverse the process of aging through gene therapy. Instead of viewing aging as an unavoidable part of life, researchers are now looking at aging as another disease to be cured. This change in perspective not only challenges the traditional progression of human life, but also the traditional structure and procedures of drug testing and regulation. With the potential for revolutionary health benefits, the U.S. Food and Drug Administration should amend current regulation to allow for the recognition of aging as a disease, as well as draft a framework to adequately assess the safety and efficacy of anti-aging gene therapies seeking FDA approval. II. Overview of Gene Therapies The prevention and treatment of human disease by gene therapy has shifted from the theoretical to the practical. Gene therapy allows medical professionals to treat disease through the modification or manipulation of gene expression in lieu of conventional pharmaceutical drugs. The first human gene therapy trial was conducted in September 1990 and involved the 1 Willie Drye, Fountain of Youth – A mythical fountain capable of preserving life has been a popular legend for centuries, NATIONAL GEOGRAPHIC, https://www.nationalgeographic.com/archaeology-and-history/archaeology/fountain-of-youth/. 1 transfer of an enzyme-coding gene into a patient that lacked this genetic expression.2 The positive results of this initial trial encouraged the scientific community to pursue gene therapy research, which led to monumental improvements and breakthroughs in gene therapy technology.3 These advancements gave rise to a variety of methodologies of achieving gene therapy. A. Current Methodologies for Gene Therapy Gene therapy involves manipulating DNA or RNA for the treatment or prevention of human disease.4 The strategies and goals of gene therapy are diverse, such as replacing or deleting genes responsible for genetic disease, producing disabling mutations in pathogen genomes to combat infection disease, or inducing therapeutic or protective somatic mutations.5 All of these strategies address the underlying genetic component of disease as opposed to treating the symptoms or managing the progression of disease. For a method of gene therapy to be deemed successful an appropriate amount of therapeutic gene must be delivered to the target cell without cellular toxicity.6 Currently, there are numerous methods of accomplishing gene therapy, and they all differ in the way of 2 A. Dusty Miller, Human Gene Therapy Comes of Age, 357 NATURE 455, 455 (1992). 3 A. Dusty Miller, 357 NATURE at 455. 4 DNA, or deoxyribonucleic acid, is a molecule composed of two strands of nucleotides that coil around each other to form a double helix carrying the genetic instructions used in the growth, functioning, and reproduction of all known organisms and many viruses. RNA, or ribonucleic acid, is a single-stranded molecule of nucleotides that acts as a messenger to carry genetic instructions from DNA to ribosomes in order to synthesize necessary proteins. ENCYCLOPEDIA BRITANNICA, https://www.britannica.com/science/DNA (last visited May 15, 2019). 5 Lu Xiao-Jie, Xue Hui-Ying, Ke Zun-Ping, Chen Jin-Lian, Ji Li-Juan, CRISPR-Cas9: A new and promising player in gene therapy,289 J. MED GENET 52 (2015). 6 Mark A. Kay, Joseph C. Glorioso & Luigi Naldini, Viral Vectors For Gene Therapy: the Art of Turning Infectious Agents into Vehicles of Therapeutics, 7 NATURE MEDICINE, 33, 33-40 (2001). 2 delivering the gene or genetic manipulation to the target cell.7 The methods that are most commonly used in anti-aging gene therapy research include: vectors, plasmid DNA, and human gene editing technologies. 1. Viral Vectors All viruses use a similar method of attacking the host cell and introducing its genetic material into the host cell as part of its own replication cycle. The genetic material introduced into the host cell contains basic instructions for how to produce more copies of the virus. Essentially, the virus hijacks the host’s normal reproduction machinery to serve the needs of the virus.8 Some strains of viruses insert its genes into the host’s genome, which leads to the genes of that virus being incorporated into the host cell’s genes for the life span of the cell. Other viruses do not insert genes into the host’s genetic makeup, but simply insert its genome into the cytosol of the host cell for the benefit of one replication cycle.9 Scientists discovered that the mechanism of viral replication could be channeled for disease prevention instead of viral infection. Certain viruses are exceptionally effective at delivering therapeutic genes to specific cell types while usually avoiding an immune response by the host.10 Scientists are capable of removing the virus’ disease causing genes and replacing those genes with desired therapeutic genes. This procedure is done in a way that does not disrupt the virus’ ability to insert this newly beneficial gene into the host cell. This makes viral vectors 7 Inder M. Verma and Nikunj Somia, Gene Therapy – promises, problems and prospects, 389 NATURE, 239 (1997). 8 Mark A. Kay, Joseph C. Glorioso & Luigi Naldini, Viral Vectors For Gene Therapy: the Art of Turning Infectious Agents into Vehicles of Therapeutics, 7 NATURE MEDICINE, 33, 33-40 (2001). 9 Id. 10 Paul D. Robbins and Steven C. Ghivizzani, Viral Vectors for Gene Therapy, 80 PHARMACOLOGY & THERAPEUTICS, 40-47 (1998). 3 an attractive gene-delivery mechanism for gene therapy. Many viruses have been modified for use in gene therapy applications, such as retrovirus, adenovirus, and herpes simplex virus.11 Each type of viral vector has its own unique advantages and limitations, which allow medical professionals to choose the viral vector best suited for the patient’s needs. For example, retrovirus vectors can permanently integrate into the genome of the host cell, which allows for long lasting expression of the desired gene; potentially up to the life cycle of the host cell.12 A limitation of retrovirus vectors is that these vectors require cell division for the genetic material to be passed along, and therefore cannot introduce genetic material into a non-dividing host cell type, such as neurons.13 Whereas, adenoviral vectors are efficient at delivering genes to a variety of dividing and non-dividing cell types, but immune response by the host often eliminates the treated cells leading to limited, transient gene expression.14 Herpes simplex virus can deliver large amounts of genetic material due to its large genetic packaging capacity, but since it does not integrate into the host cell’s genome the desired gene expression is temporary.15 Therefore, the variety of viral vectors allows for a range of applications from genetic packaging capacity, host cell range, cell- or tissue-specific targeting, genome integration, and duration of gene expression.16 A genetic therapist can select the viral vector that is most suitable for the patients needs. 2. Bacterial Vectors 11 Paul D. Robbins and Steven C. Ghivizzani, Viral Vectors for Gene Therapy, 80 PHARMACOLOGY & THERAPEUTICS, 40-47 (1998). 12 Id. at 45. 13 Paul D. Robbins and Steven C. Ghivizzani, 80 PHARMACOLOGY & THERAPEUTICS at 45. 14 Id. 15 Id. 16 Kenneth Lundstrom, Latest Development in Viral Vectors for Gene Therapy, 21 TRENDS IN BIOTECHNOLOGY, 117 (2003). 4 Like viruses, the innate biological mechanisms of bacteria allow efficient DNA delivery to cells and tissues within a host.17 Bacteria are considered “non-viral” vectors. Bacteria naturally contain plasmids, which are small, circular DNA molecules that are distinct from a cell’s chromosomal DNA. Researchers can introduce plasmids with desired genes into the bacteria, which are then introduced into the targeted host cell. Bacterial vectors insert genetic material into mammalian cells through entry of the entire bacterium into the target cell.18 Target cells recognized the bacteria as a foreign body and engulf the bacteria for degradation through a process called phagocytosis. Once inside the target cell, the bacteria is localized within the target cell’s phagosome, which is a vesicle in the cell’s cytoplasm. 19 Phagosomes have membrane-bound proteins that recruit and fuse with lysosomes, which contain hydrolytic enzymes that kill and digest pathogens, such as bacteria. Once the bacterial vector is digested, the plasmid DNA within the bacteria that carries the desired gene is then released into the host cell’s cytosol. The newly introduced plasmid DNA makes its way into the target cell’s nucleus, most likely during mitosis, where it is then replicated and the desired gene is expressed using the host cells machinery.20 3. Plasmid DNA Plasmid DNA can be introduced into a host cell through the use of a bacteria vector or it can be introduced by itself through other laboratory means. A plasmid is a small, circular DNA molecule that is physically separated from chromosomal DNA and can replicate independently. 17 Chwanrow K. Baban et al., Bacteria as Vectors for Gene Therapy of Cancer, 6, BIOENGINEERED BUGS, 385-387 (2010). 18 Georges Vassaux, Josianne Nitcheu, Sarah Jezzard, and Nick R Lemoine, Bacterial Gene Therapy Strategies, 208 J PATHOL, 290, 290-298 (2006). 19 Id. 20 Id. 5 Artificially produced plasmids can be constructed to contain a desired gene that will be amplified once introduced into the targeted host cell.

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