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.

Researchers identified numerous physical methods to deliver the plasmid vector into the targeted host cell. First, plasmid DNA can simply be carried out through intramuscular injection of the naked DNA plasmid; however, this method only leads to minimal expression of the gene.

Electroporation is another method that uses short pulses of high voltage electricity to carry the plasmid DNA across the cell membrane. The electric shock causes the formation of temporary pores on the cell membrane that allow the small plasmid DNA to pass through. Similarly, sonoporation uses ultrasonic frequencies to disrupt the host cell membrane and allow the delivery of the plasmid DNA. Lastly, the use of a gene gun involves coating the plasmid DNA with gold particles and loading it into the device that generates a force allowing the plasmid

DNA to enter the host cell while leaving the gold behind on a “stopping” disk.

Utilizing plasmid DNA as a vector circumvents some of the problems associated with viral and bacterial vectors, such as endogenous virus recombination, oncogenic effects, and unforeseen immune responses.21 The additional advantages of using plasmid DNA include: simplicity of use, ease of large-scale production, and lack of specific genetic side effects.22 A drawback is that the levels of expression of the desired gene carried on the plasmid are much lower than that of viral or bacterial vectors.23

4. Human Gene Editing Technology

Targeted human genome editing using programmable, engineered nucleases is rapidly transforming gene therapy technology. Genome editing with nucleases, such as zinc finger

21 T Niidome and L Huang, Gene Therapy Progress and Prospects: Nonviral Vectors, GENE THERAPY, 1647-1652 (2002). 22 Id. 23 Id. 6 nucleases (ZFNs), enable a range of genome manipulations in a site-specific manner.24 Zinc finger nucleases are artificial enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be created to target specific DNA sequences, which allows the enzyme to make specific cuts in the genome and allow the cell’s own DNA repair machine to correct a disease causing genetic mutation. These manipulations include gene activation or inactivation, sequence deletion, and chromosomal rearrangement through the “cut-and-paste” strategy of programmable nucleases.25

The most recent and notable programmable nuclease is the RNA-guided editing tool termed CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR- associated nuclease 9). These repeats in the genetic code allow for RNA guided nucleases

(RGNs), such as Cas9, to cut precisely at that point and allow for the input of a new DNA sequence. Researchers can create a small piece of RNA with a guide sequence that attaches to a specific target sequence of DNA in a host’s genome. This small piece of RNA also binds to the

Cas9 enzyme. Cas9 then cuts the DNA sequence and researchers can use the cell’s own DNA repair machinery to add or delete pieces of DNA sequence or make changes to the DNA by replacing the portion excised with a customized DNA sequence. This “cut and paste” ability allows researchers to modify endogenous genes that have been traditionally difficult to manipulate genetically.26

B. Anti-Aging Gene Therapies

Anti-aging gene therapies use similar biological mechanisms and vector methodologies as traditional gene therapies, but the therapeutic goals are different and broader. The main

24 Lu Xiao-Jie, et al. 52 J MET GENET at 289. 25 Id. 26 Id. 7 difference is that anti-aging gene therapies seek to reverse or delay all age-related diseases, whereas traditional gene therapies focus on one therapy for one disease.27 This difference in therapeutic effect and patient treatment plan is revolutionary; however, this ability to treat multiple diseases simultaneously leads to regulatory issues.

Researchers have identified two main approaches of harnessing genetic engineering to reverse or delay the cellular changes associated with aging, which consist of telomerase inducement and selective destruction of senescent cells. Both approaches utilize gene manipulation to potentially extend human life through reversing cellular changes seen in mature individuals, and thus preventing age-related disease associated with these cellular changes.

1. Telomerase Inducement

The first method, telomerase inducement, focuses on prolonging the healthy life of a cell through elongation of the telomere region of chromosomes.28 Telomeres are the regions of repetitive DNA (TTAGGG) repeats at the end of chromosomes, which are known to protect the chromosome from deterioration or fusion with neighboring chromosomes.29 The DNA repeats shorten with each cell division due to chromosomal end replication problems, oxidative damage, and other poorly understood mechanisms.30 When telomeres become critically shortened there is an arrest in the growth state and cellular senescence is triggered. Cellular senescence is a process in which cells stop dividing and undergo distinctive phenotypic changes, such as chromatin changes and tumor-suppressor activation, which halts normal

27 Alvin Powell, Longevity and Anti-Aging Research: ‘Prime Time for an Impact on the Globe,’ THE HARVARD GAZETTE (Mar. 8, 2019), https://news.harvard.edu/gazette/story/2019/03/anti- aging-research-prime-time-for-an-impact-on-the-globe. 28 Jerry W. Shay, Role of Telomeres and Telomerase in Aging and Cancer, CANCER DISCOVERY 584, 584 (2016). 29 Id. at 584. 30 Id. 8 cellular functioning.31 Senescent cells do not automatically undergo self-degradation and death, but instead continue to exist in this damaged state and may secrete factors that promote age- related diseases, such as osteoarthritis, pulmonary fibrosis, atherosclerosis, and Alzheimer’s disease.32 Thus, researchers are pursuing methods to reverse the shortening or promote the elongation of telomeres in order to prevent or delay the onset of cellular senescence.

Telomerase adds new DNA repeats onto the telomere region of chromosomes, and thus promotes continued cell division and prevents cellular senescence.33 Telomerase is regularly activated in germline, hematopoietic, stem cell, and rapidly renewing cell types (like basal skin layer cells, endometrial tissue, and hair follicles).34 Additionally, telomere length and telomerase activity diverge between normal and embryonic stem cells. Embryonic stem cells, essentially immortal cell lines, maintain their telomere length and exhibit telomerase activity, whereas normal stem cells have progressive telomere shortening and minimal telomerase activity.35 In fact, increased telomerase activity in normal stem cells might be useful marker for cancer diagnosis because cancer arises when normal cells accumulate genomic instability, limitless proliferation capacity, and bypass cellular senescence.36

Researchers studies are attempting to harness the anti-aging potential of telomerase by utilizing adeno-associated virus (AAV) vectors to transfer the telomerase gene into specific cells.37 AAVs have become the vector of choice for gene transfer because they are non-

31 Jan M. van Deursen, The Role of Senescent Cells in Ageing, 509 NATURE 439, 440-43 (2014). 32 Id. at 445. 33 Id. 34 Id. 35 Id. at 446-47. 36 Id. 37 Bruno Bernardes de Jesus, et al., Telomerase Gene Therapy in Adult and Old Mice Delays Aging and Increases Longevity Without Increasing Cancer, 4 EMBO MOL MED, 691, 692 (2012). 9 integrative, but sustain long-term gene expression (up to several years).38 Ideally, this limit on telomere extension would promote telomere extension, cell rejuvenation, and extended cell life, but not induce the cell to become cancerous by performing uncontrolled, defective cell division.

Current animal studies have shown that telomerase expression through gene therapy later in life can re-activate telomerase activity in a range of tissues and have beneficial effects on age- related disease; such as improved metabolic function and improved neuromuscular coordination.39 Overall, this telomerase gene therapy is a novel type of therapeutic intervention that has the possibility of repairing or delaying the accumulation of DNA damage, promoting extended, healthy cell division, and increasing the average lifespan, as well as health of aged organisms.

2. Selective Destruction of Senescent Cells

On the other side of the coin, many researchers are focusing on removing accumulated senescent cells as opposed to preventing senescent cells in order to delay age-related disease.

Senescent cells are in a state of irreversible replicative arrest and no longer undergo cellular division, but are also resistant to programmed cell death and degradation, known as apoptosis.40

While in this “zombie-like” state, senescent cells secrete factors, such as cytokines and other pro- inflammatory mediators that are referred to as the senescence-associated secretory phenotype

(SASP).41 The SASP can contribute to tissue and joint inflammation, metabolic regulation issues, aging phenotypes, chronic disease, and geriatric syndromes.42 Therefore, removing senescent

38 Id. at 692. 39 Id. at 699. 40 Jan M. van Deursen, 509 NATURE at 440-43. 41 James L. Kirkland & Tamara Tchkonia, Cellular Senescence: A Translational Perspective, 21 EBIO MED 21, 21-22 (2017). 42 Id. at 21. 10 cells from tissues throughout the body through targeted apoptosis mechanisms is a promising anti-aging therapy.

Research groups are pursuing both pharmaceutical and gene therapy methodologies of targeting and inducing the apoptosis of senescent cells. Of the gene therapies, one mechanism includes the targeting of senescent cells through the use of a biomarker for senescence, p16(Ink4a).43 Researchers designed a novel gene, INK-ATTAC, which promotes programmed cell death and is integrated into a vector that selectively targets p16(Ink4a)-positive senescent cells.44 Through previously explained vector mechanisms, INK-ATTAC is introduced into the targeted senescent cell and the cell’s own machinery induces the expression of INK-ATTAC.45

The expression of INK-ATTAC encodes a protein, which eliminates the senescent cell by inducing cell death through apoptosis.46 Early animal studies show that non-senescent cells are unaffected, while there is a significant decrease in p16(Ink4a)-positive senescent cells and associated harmful secretions.47

The removal of senescent cells and telomerase inducement are related, but different approaches to solving the same problem of cellular aging and subsequent age-related disease.

The potential of extending not only the length, but also quality of human life through these genetic therapy methodologies spurred a wave of private and non-profit research groups.

III. Many Private Companies Are Already Developing Anti-Aging Gene Therapies

43 DJ Baker et al., Clearance of p16Ink4a-positive Senescent Cells Delays Ageing-Associated Disorders, 479 NATURE 232-36 (2011). 44 Id. at 234. 45 Id. 46 Id., See Sys. & Methods for the Targeted Production of a Therapeutic Protein within a Target Cell, U.S. Patent App. No. US14/779,565 (filed Mar. 24, 2014). 47 DJ Baker et al., 479 NATURE at 235-36. 11

While still in the early stages of development, many companies are investing tremendous resources in anti-aging gene therapies. Privately funded companies are attempting to get a jump on the market even though clinical implications are most likely many years away and will require years of clinical trials before potential FDA approval and public marketing. Two of the leading companies pursuing anti-aging gene therapies include: Oisin Biotechnologies and Sierra

Sciences.48

A. Oisin Biotechnologies

Oisin Biotechnologies is a privately funded research company based in Seattle,

Washington. Oisin researchers are attempting to mitigate the effects of age-related diseases by addressing the cellular damage of aging through the removal of senescent cells.49 Oisin is developing a patent-pending, DNA-targeted intervention that selectively targets and clears senescent cells.50

Oisin’s published patent application has entered the national phase of the PCT application process and is awaiting issuance in the United States.51 The pending patent claims a method of selecting for p16-positive senescent cells, inserting a transcriptional promoter gene into the selected senescent cell through a vector, and that promoter gene induces the production of a therapeutic protein leading to the apoptosis of the senescent cell.52 Oisin claims to have demonstrated the ability to insert the promoter gene into p16-positive senescent cells both in cell

48 Joao Pedro de Magalhaes, Michael Stevens & Daniel Thornton, The Business of Anti-Aging Science, 35 TRENDS IN BIOTECHNOLOGY 1062, 1063-65 (2017). 49 OISIN BIOTECHNOLOGIES, https://www.oisinbio.com (last visited Apr. 14, 2019). 50 Id. 51 Sys. & Methods for the Targeted Production of a Therapeutic Protein within a Target Cell, U.S. Patent App. No. US14/779,565 (filed Mar. 24, 2014). 52 Id. 12 culture and in mice.53 The company is now collecting data to prove this mechanism improves both health and lifespan in mammals.

B. Sierra Sciences

Sierra Sciences is a biotech company based in Reno, Nevada that holds the primary mission of extending the quality and quantity of human life through telomere maintenance.54

Sierra Sciences believes that a gene therapy that stops the repression of telomerase enzymatic activity within cells will reverse the cellular aging process and prevent age-related diseases.55

The current focus of Sierra Sciences is researching genetic compounds that will block the repressor protein from binding to the DNA site in order to promote the cells natural telomerase activity, which will extend telomere length.56

Dr. William Andrews, the leading scientist at Sierra Sciences, has applied for a total of nineteen patents all related to modulating telomerase reverse transcriptase or telomerase expression repressor proteins and methods of use.57 Five of the nineteen published patent applications have been granted and issued, as well as assigned to Sierra Sciences, LLC.58 The most recently issued patent, “Enhancing Health in Mammals Using Telomerase Reverse

Transcriptase”, claims methods of treating an age-related disorder through administering a

53 OISIN BIOTECHNOLOGIES, https://www.oisinbio.com (last visited Apr. 14, 2019). 54 SIERRA SCIENCES, https://www.sierrasci.com (last visited Apr. 15, 2019). 55 Id. 56 Id. 57 Id. 58 Methods and Compositions for Modulating Telomerase Reverse Transcriptase (TERT) expression, U.S. Patent No. 6,686,159 (issued Feb. 3, 2004); Telomerase Expression Repressor Proteins and Methods of Using Same, U.S. Patent No. 7,795,416 (issued Sept. 14, 2010); Methods and Compositions for Modulating Telomerase Reverse Transcriptase (TERT) Expression, U.S. Patent No. 7,279,328 (issued Oct. 9, 2007); Assays for TERT Promoter Modulatory Agents Using A Telomerase Structural RNA Component, U.S. Patent No. 7,226,744 (issued June 5, 2007); Enhancing Health in Mammals Using Telomerase Reverse Transcriptase Gene Therapy, U.S. Patent No. 9,453,209 (issued Sept. 27, 2016). 13 nucleic acid vector that includes a coding sequence for telomerase reverse transcriptase

(TERT).59 The patent also claims the methods may lead to increased expression of TERT, which promotes telomere elongation and amelioration of markers of aging, including by not limited to osteoporosis, memory loss, and neuromuscular degeneration.60

Sierra Sciences’ growing patent portfolio puts it in an advantageous and potentially lucrative position if these telomere extending gene therapies ultimately get FDA approved. Sierra

Sciences admits that it will take many years to bring a telomerase inducer through the FDA approval process and then to market.61

IV. Current Gene Therapy Regulation in the United States

In the United States, the Department of Health & Human Services is charged with the regulation and oversight of gene therapy clinical trials. The U.S. Department of Health & Human

Services is in place to protect the health of all Americans by providing effective health and human services, and promoting advancements in medicine and public health. Two organizations within the Department of Health & Human Services, the Office for Human Research Protections and the U.S. Food and Drug Administration (FDA) have specific authority as described in the

Code of Federal Regulations (CFR) to regulate clinical gene therapy trials. Specifically, the U.S.

Federal Food, Drug, and Cosmetic Act passed by Congress in 1938 gives authority to the FDA to oversee the safety of food, drugs, medical devises, and cosmetics.62

The FDA is responsible for protecting the public’s health through ensuring the safety and efficacy of human drugs, biological products, and medical devices. FDA’s Center for Biologics

59 Enhancing Health in Mammals Using Telomerase Reverse Transcriptase Gene Therapy, U.S. Patent No. 9,453,209 (issued Sept. 27, 2016). 60 Enhancing Health in Mammals Using Telomerase Reverse Transcriptase Gene Therapy, U.S. Patent No. 9,453,209 (issued Sept. 27, 2016). 61 SIERRA SCIENCES, https://www.sierrasci.com (last visited Apr. 15, 2019). 62 21 U.S.C. § 301 et seq. (1938). 14

Evaluation and Research (CBER) regulates human gene therapies, which fall within the scope of

“biologics” as defined by the FDA. CBER relies on the Public Health Service Act and the

Federal Food, Drug, and Cosmetic Act as enabling statutes for oversight.63

A. FDA’s Gene Therapy Approval Process

Manufacturers of gene therapy products must test their products and meet FDA requirements for safety, purity and potency before they can be sold in the United States. The following steps must be followed in order to obtain FDA drug approval, which include a pre- clinical phase, a clinical phase, New Drug Application review, and post-marketing review.64

First, the pre-clinical phase requires the gene therapy developer to tell FDA of its intentions, test the therapy in a laboratory, and then test the therapy animal studies.65 The developer must test the proposed new gene therapy on multiple species of animals in order to assess the toxicity, safety, and efficacy of the therapy. After successfully completing animal studies, the gene therapy developer must submit an Investigational New Drug (IND) application to the FDA that includes the gene therapy’s composition and manufacturing, as well as develop a plan for testing the drug on humans.66 The IND must also state what possible risks may be involved and what steps it will take to protect patients, and provides data in support of the study.

As part of the IND process, the gene therapy developer must also get approval from a committee of scientific and medical advisors and consumers, called an Institutional Review Board, which

63 CELLULAR AND GENE THERAPY PRODUCTS, https://www.fda.gov/vaccines-blood- biologics/cellular-gene-therapy-products (last visited May 13, 2019). 64 U.S. FOOD AND DRUG ADMINISTRATION – DRUG APPROVAL PROCESS, https://www.fda.gov/media/82381/download (last visited May 10, 2019). 65 David A. Kessler et al., Regulation of Somatic-Cell Therapy and Gene Therapy by the Food and Drug Administration, 329 N. ENGL. J. MED. 1169, 1170-73 (1993). 66 Id. at 1172. 15 focuses on protecting persons who may participate in the study.67 Researchers also must inform the persons who may be part of the study about the study's potential risks and benefits, and obtain their consent.

Once the FDA approves the IND, the proposed gene therapy can move onto the clinical stage of the approval process.68 The clinical stage includes three phases of clinical studies and trials. Phase 1 entails administering the gene therapy to a group of 20-80 healthy volunteers in order to determine the drug’s most frequent side effects, as well as how the drug is metabolized and excreted.69 This phase of clinical trials emphasizes the FDA’s commitment to safety. Phase 2 involves a group of 100 or more patients that suffer from a certain disease that the gene therapy claims to improve.70 The goal of phase 2 is to obtain preliminary data on if the gene therapy actually improves the patient’s condition when compared to a similar patient that is receiving a placebo therapy. The goal of this phase is to ascertain the effectiveness of the proposed gene therapy. Phase 3 of clinical trials includes thousands of patients and is used to gather more information on the safety and effectiveness of the drug across different populations, different dosages, and uses of the therapy in combination with other drugs.71

The gene therapy developer must then submit a New Drug Application (NDA) for review by CBER scientists. The NDA includes all animal and human trial data, as well as how the therapy behaves in the human body and how the therapy is manufactured.72 CBER scientists review the NDA and have 60 days to decide if they will file and approve the NDA. If approved,

67 David A. Kessler et al., 329 N. ENGL. J. MED. at 1172. 68 Id. 69 Id. 70 Id. 71 Id. 72 Id. at 1173. 16 the FDA then reviews the therapy’s professional labeling and assures appropriate information is communicated to heath care professionals and consumers.

The final phase of the gene therapy approval process includes post-marketing approval and risk assessment. Here, the gene therapy developer is required to submit periodic safety updates to CBER.73 The FDA requires this phase because it is impossible to predict all of the gene therapy’s effects during clinical trials. If CBER determines there is a serious, unexpected adverse event, then it can pull the gene therapy from production and administration.

The FDA is the main hurdle for all gene therapy research groups and corporations that are seeking clinical trial approval and marketability. The FDA released a guidance statement on

July 11, 2018, which addressed the FDA’s concerns with gene therapy.74 Most notably the FDA is concerned with gene therapy manufacturing, as well as the quality and durability of response.

The FDA is concerned with these aspects of gene therapies because these questions usually cannot be fully answered in any reasonably sized pre-market trial.75 The FDA guidance statement goes on to suggest adding reliable and extensive post-market safety updates to ensure the safety of these innovative gene therapies.76 The FDA has only approved approximately 16 cellular and gene therapy products to date, which include treatments for hemophilia, retinal

73 David A. Kessler et al., 329 N. ENGL. J. MED. at 1173. 74 STATEMENT FROM FDA COMMISSIONER SCOTT GOTTLIEB, M.D. ON AGENCY’S EFFORTS TO ADVANCE DEVELOPMENT OF GENE THERAPIES, https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm613026.htm (last visited Apr. 17, 2019). 75 Id. 76 Id. 17 disorders, and rare diseases as defined by the Orphan Drug Act of 1983 (disorders affecting fewer than 200,000 persons in the United States).77

V. Current FDA Regulation Does Not Recognize Aging as a Disease

The central goal of anti-aging gene therapy is to treat and prevent the degenerative effects and chronic diseases associated with aging. These gene therapy treatments face a somewhat insurmountable regulatory hurdle in that the FDA does not recognize aging as a disease that requires therapeutic intervention. The FDA has never allowed clinical testing nor approved a drug that aims to treat the systemic effects of aging because the FDA does not consider the natural process of aging to be a disease.78

The FDA defines disease in the following way:

…a ‘disease’ is damage to an organ, part, structure, or system of the body such that it does not function properly (e.g., cardiovascular disease), or a state of health leading to such dysfunctioning (e.g., hypertention); except that diseases resulting from essential nutrient deficiencies (e.g., scurvy, pellagra) are not included in this definition.79

One would interpret aging to fit into this definition because it is a “state of health leading to such dysfunctioning.” The FDA has nevertheless stipulated that aging is not a disease, but a natural state of human life.80 Therefore, conditions associated with certain “natural states” are not diseases.

77 See APPROVED CELLULAR AND GENE THERAPY PRODUCTS, https://www.fda.gov/vaccines- blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products (last visited May 14, 2019). 78 Sarah Karlin-Smith, Why a drug for aging would challenge Washington, POLITICO (Dec. 13, 2017), https://www.politico.com/agenda/story/2017/12/13/anti-aging-research-drugs-000595. 79 21 C.F.R. § 101.93(g) (2012). 80 Peter Barton Hutt, FOOD AND DRUG LAW, 40 (3d ed. 2007). 18

Furthermore, evaluating the science and quantifying the benefits of anti-aging gene therapies adds complexity and uncertainty to the FDA’s current assessment and regulation procedures.81 This is because it is difficult to measure if a gene therapy is fundamentally changing the course of human aging and ameliorating a wide range of age-related diseases. The number of variables and genetic predispositions of each individual participant could skew the results into appearing more positive then in actuality.82 Additionally, the FDA is unclear on the length of time the clinical trials should run for anti-aging gene therapies. Decade long studies could potentially be required in order to see the full benefits and risks of these anti-aging gene therapies.83 Therefore, the FDA’s central goals of safety and efficacy are fraught with ambiguity when considering anti-aging gene therapies.

Additionally, the FDA would be divided on approving these anti-aging gene therapies for human clinical trials in healthy, middle-aged subjects because the benefits have only been seen in animal models with a shortened life span and it is unknown if these genetic manipulations will be inheritable from generation to generation.84 Scientists are considering how to circumvent some of these regulatory hurdles, which includes testing these gene therapies in only very sick individuals in order to see if there is an amelioration of chronic disease.85 The idea being to get anti-aging gene therapies approved under more traditional protocols, specifically the one therapy treating one disease methodology, but effectively open the door to the idea of treating aging as a disease.

81 Sarah Karlin-Smith, Why a drug for aging would challenge Washington, POLITICO (Dec. 13, 2017), https://www.politico.com/agenda/story/2017/12/13/anti-aging-research-drugs-000595. 82 Id. 83 Id. 84 Id. 85 Id. 19

VI. Proposed New Regulation to Allow for Anti-Aging Gene Therapy Testing and Approval

The United States current regulatory agencies are unable to assess the safety and efficacy of anti-aging gene therapies. This is mainly because of the dilemma of whether or not to consider aging a disease or a natural state. Additionally, drafting a new regulatory and approval framework to quantify the benefits of these therapies is another hurdle for lawmakers. For the purposes of medical advancement and age-related disease treatment, the FDA should start the process of making regulatory changes to allow for clinical testing of anti-aging gene therapies and eventually approval of certain therapies.

The United States should look to the current protocols of Australia as a guide to amend regulatory framework in order to properly assess anti-aging gene therapies and monitor for safety compliance strictly in clinical trials. Australia currently does not consider ageing a disease, much like in the United States; however, it does have a regulatory framework in place to allow for clinical testing of anti-aging gene therapies. In Australia, all human clinical trials must be conducted under a Clinical Trial Exemption (CTX) and are overseen by the Therapeutic Goods

Administration (TGA).86 Under the CTX framework, the proposed gene therapy clinical trial is reviewed by the TGA and may not proceed until approval is granted. The CTX protocols are equipped to handle experimental testing that includes new technology or new treatment concepts that have not been previously evaluated in other countries or tested on humans.87 This framework opens the door to experimental treatments that are most likely too risky under current FDA regulation.

86 AUSTRALIAN GOVERNMENT - DEPARTMENT OF HEALTH, http://www.health.gov.au/internet/main/publishing.nsf/Content/Gene%20Technology-2 (last visited Apr. 16, 2019). 87 Id. 20

In Australia, trials involving gene therapy also require approval under the Gene

Technology Act 2000, which is administered by the Gene Technology Regulator.88 Additionally, recent changes to regulation in 2018 reflect the increase in human biologics and genetic therapies.89 Clinical trials regarding genetic therapies must be classified under 1 of 4 categories, which correspond to the amount of risk associated with the trial.90 For example, Class 1 and 2 are minimally genetically manipulated products; Class 3 includes biological prepared using more complex methods, such as the treatment of skin disease with mesenchymal stem cells; and Class

4 includes all high-risk trials, such as genetic modification.91 Therefore, anti-aging gene therapies would most likely fall under Class 4. Each of the tested products within these categories must comply with all specific reporting requirements of the TGA.

Australia’s regulatory scheme provides a framework for the United States to use as a foundation for new regulation regarding assessing anti-aging gene therapies in clinical trials; however, there still remains the question of treatment approval and marketing. The United States

FDA and lawmakers will have to accept aging as a disease in order for gene therapies to be approved and marketed as a treatment for a variety of age-related disease. This is a radical step; however, the FDA should consider changing its perspective on aging from a natural state to a disease. This would allow the FDA to regulate anti-aging gene therapy clinical trials, as well as approval and post-approval safety measures. If the FDA is adamant in not considering aging to

88 GENE TECHNOLOGY ACT 2000, No. 169, 2000 (2016). 89 Sally J. Davis, Michael Caine, & Alex Tzanidis, Proposed Changes to the TGA Regulatory Framework for Biologicals – Capturing Autologous Cell Therapies Within the ARTG, (May 16, 2018), https://s3.amazonaws.com/documents.lexology.com/cd6e02b2-e7af-434b-9c6c- fdef36a67558.pdf 90 Sally J. Davis, Michael Caine, & Alex Tzanidis, Proposed Changes to the TGA Regulatory Framework for Biologicals – Capturing Autologous Cell Therapies Within the ARTG, (May 16, 2018), https://s3.amazonaws.com/documents.lexology.com/cd6e02b2-e7af-434b-9c6c- fdef36a67558.pdf 91 Id. 21 be a disease, then anti-aging research groups may pivot towards producing anti-aging supplements that do not require FDA approval to be marketed. It is in the FDA’s interest to negotiate and work with anti-aging gene therapy developers to create new regulation that would acknowledge aging as a disease, but also put in place stringent clinical testing protocols and safety reporting for the length of the participant’s lives. Science and medicine continue to evolve and corresponding regulation should do the same.

VII. Conclusion

The advancements made and continuing to be made in anti-aging gene therapies may allow not only for the extension of life, but also the extension in quality of life. It is both revolutionary and controversial to consider aging to be a disease, but aging and age-related diseases are medical concerns that every individual must face in their lifetime. The FDA should recognize the shift in medicine and technology and create a new framework that loosens the regulatory framework of “one therapy for one disease” and allow for the testing and potential approval of multifaceted anti-aging gene therapies.

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