U.S. Regulatory Challenges for Gene Editing

Current gene editing technology improves on prior cellular-based therapies and gene therapies because it directly targets the defective gene or certain nucleotides within the gene. Following the discoveries of zinc finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN), a technique known as clustered regularly interspaced short palindromic repeat (CRISPR) is the most precise, efficient, and least expensive method of gene editing to date. First described in 2012, CRISPR/Cas9 uses the Cas9 enzyme and an RNA guide sequence to target a particular gene sequence, remove the faulty DNA segment, repair the defect or insert a new functioning gene, and fuse the genetic strand(s) back together.¹ New variants of the CRISPR technology are currently being explored.

CRISPR is garnering significant attention in the United States for both its relative simplicity over previous gene editing techniques and for its potential long-term commercial impacts. Shortly after the publication of the CRISPR discovery in Science,² several leading gene editing scientists formed Editas Medicine in Cambridge, Massachusetts, with a $43 million capital investment to design clinical trials based on the CRISPR and TALEN platforms. Reports indicate that Editas is projected to begin clinical trials by 2017 for a rare retinal disorder called Leber congenital amaurosis.³ But Editas is not the only player. Many of the early researchers involved in developing the CRISPR technology, including Jennifer Doudna (Caribou Biosciences) and Emmanuelle Charpentier (CRISPR Therapeutics) have also formed companies to develop applications using the CRISPR system. In June 2016, the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC) approved a University of Pennsylvania protocol applying CRISPR to genetically modify human T cells in 15 individuals suffering from multiple myeloma, melanoma, and sarcoma. Funded by the new Parker Institute for Cancer Immunotherapy, and led by Dr. Carl June, the clinical trial protocol has yet to be reviewed and approved by the appropriate institutional bodies and the U.S. Food and Drug Administration (FDA).⁴

Although in early stages of regulatory approval, the June 2016 decision of the RAC sheds new light on the ongoing debate regarding the ethical and legal implications of gene editing research. Concern about gene editing has inspired a broad global discussion in scientific and bioethics communities as to proper regulation and whether to halt future research on germline, or heritable, applications. This global discussion is nestled in the rich history of genetic research and the existing federal frameworks in place to oversee clinical trials, as well as the distinction between somatic and germline interventions. This article will examine the current regulatory landscape for gene editing research in the United States as positioned within the historical context and recent developments in this area.

Gene Editing Techniques and Clinical Applications

The June 2016 RAC-approved study is preceded by several other important developments in the field of gene editing. Three leading techniques have emerged that all use a restriction enzyme, or nuclease, to cut DNA at a specific site: ZFN, TALEN, and CRISPR. Each has varying levels of real-world clinical applications, but are all premised on the cleavage of a discrete portion of DNA that codes for a gene in order to replace or repair the gene. Several FDA-approved clinical trials involving ZFN are presently underway in the United States, sponsored by Sangamo BioSciences and led by Dr. Carl June at the University of Pennsylvania. These include clinical trials on HIV/AIDS, hemophilia B, beta thalassemia, and mucopolysaccharidosis types I and II (both lysosomal storage disorders). Early findings from the HIV/AIDS trials are published in leading medical journals. TALEN was recently approved by the United Kingdom Human Fertilisation and Embryology Authority (HFEA) as a therapeutic intervention by physicians on a one-year-old child with acute lymphoblastic leukemia at the Great Ormond Street Hospital for Children in London; the patient is now in remission.⁵ Cellectis, a French biotechnology company, has announced the start of a clinical trial using TALEN to treat 10 patients with acute lymphoblastic leukemia at University College of London.⁶

Due to the ease of use, efficiency, and precision of the CRISPR system—as compared to ZFN and TALEN—it presents tremendous potential for application in germline alteration of heritable traits. While the RAC-approved study involves somatic, or nonheritable, modifications, three other high-profile studies involve modifications to human embryos. In February 2016, the HFEA approved CRISPR/Cas9 research in human embryos at the Francis Crick Institute in London to study causes of infertility. The study is the first approved for human embryonic research in the United Kingdom using gene editing and is limited to 14 days, a restriction set forth by international policy.⁷ More recently, two groups of Chinese researchers have already employed CRISPR/Cas9 to genetically alter specific genes in nonviable human embryos; they published these results in April 2015 and March 2016.⁸

History and Regulation of Genetic Research

The concept of genetic modification is not new, but the precision, specificity, and techniques have evolved rapidly. Two critical discoveries have inevitably shaped the regulatory landscape: rDNA technology and gene transfer (also known as gene therapy) research. Over 40 years ago, the ability to cut and recombine portions of DNA residing in bacterial cells using a protein called a restriction enzyme became known as rDNA technology. The novelty and uncertainty regarding the safety implications of rDNA technology led to a 1974 temporary moratorium in the United States by a newly formed federal advisory committee, now known as the RAC, which plays a key role in the assessment of U.S. genetic research. A subsequent conference in Asilomar, California, in 1975 resulted in guidelines to ensure responsible development of rDNA research.

In 1999, the death of a subject enrolled in a gene transfer trial at the University of Pennsylvania prompted intense scrutiny of the relationship and responsibilities among institutional review boards (IRBs), the RAC, and the FDA. There, 18-year-old Jesse Gelsinger died as a result of a viral vector administered as part of the clinical trial. Investigations later revealed underlying conflicts of interest, an improper informed consent process and protocol, and serious shortcomings in communications among the sponsors, research investigators, and subjects about risks and adverse events. Today, Gelsinger’s death remains a tragic example of inherent failures in the U.S. regulatory system, and is the touchstone example for precaution in gene transfer trials.

The regulation of somatic gene editing is an extension of the regulation of gene transfer research. As a result of rDNA technology and gene transfer trials, we have in place a regulatory system consisting of three basic complementary and overarching frameworks for somatic gene transfer research: review and approval from the RAC, review and approval by one or more IRBs affiliated with the sponsor institutions, and review and approval by the FDA. Federal regulations and guidelines apply to each entity, and a sponsor must typically achieve approval from all three in order to initiate clinical trials. The RAC and IRB requirements apply to any institution receiving federal funds for research, while FDA requirements apply to any research conducted in the process of acquiring market approval for an FDA-regulated commercial product. Technically, private institutions are not subject to the RAC-IRB-FDA framework, yet adherence is the norm; market entry of any commercial drug, device, or biologic product always requires affirmative FDA review and approval or clearance.

The RAC serves as a federal advisory committee to the NIH director. Review involves scrutiny of basic and clinical research involving recombinant or synthetic nucleic acid molecules under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules and other relevant NIH policy. IRB review, on the other hand, involves professional bodies within the sponsoring institutions and deals largely with sponsor and investigator qualifications, clinical trial facilities and staff, study design, clinical trial protocol, informed consent, conflicts of interest, reporting mechanisms, and other related matters. All cellular and gene therapy products are subject to approval by the FDA through the investigational new drug (IND) process either as a biologic or a drug, or both. The FDA defines a gene therapy product as “products containing genetic material administered to modify or manipulate the expression of genetic material or to alter the biological properties of living cells.”⁹ FDA-specific human subject regulations apply to all clinical trials. Eventual product approval requires satisfactory clinical trial results evincing safety and efficacy, as well as adherence to good manufacturing practices, proper labeling, and postmarket reporting. The FDA maintains a website detailing the process and requirements, including regulatory information and guidance documents.¹⁰

Overall, somatic gene editing can be, and is being, evaluated on a case-by-case basis by regulators in the United States and internationally. However, there is some concern over applying gene editing techniques to basic embryo research, and widespread concern over introducing gene editing into the human germline through clinical interventions. Similar to the response to rDNA technology in the 1970s, prominent scientists have called for a moratorium on gene editing of the human germline in various public outlets, citing both safety and ethical issues.¹¹ One joint position put forth by 18 scientists, lawyers, and ethicists recommends that steps must be taken to “[s]trongly discourage, even in those countries with lax jurisdictions where it might be permitted, any attempts at germline genome modification for clinical application in humans.”¹² Both UNESCO’s International Bioethics Committee and the International Society for Stem Cell Research also recommended an international moratorium on gene editing of the human germline. In efforts to explore these concerns and various ethical positions, several scientific organizations have hosted events, including the U.S. National Academies of Sciences, Engineering, and Medicine and the Federation of European Academies of Medicine.

Regulation of Germline Gene Editing

In contrast to somatic changes, human embryonic research and germline interventions raise several important legal limitations in the United States. Issues of heritability to offspring are the critical factor in discussions of ethical and legal implications of germline gene editing, as is the ethically charged issue of the conduct of basic embryonic research to develop and refine proper germline techniques. The NIH Guidelines differentiate somatic and germline gene transfer in the following manner:

The purpose of somatic cell gene transfer is to treat an individual patient, e.g., by inserting a properly functioning gene into the subject’s somatic cells. Germ line alteration involves a specific attempt to introduce genetic changes into the germ (reproductive) cells of an individual, with the aim of changing the set of genes passed on to the individual’s offspring.¹³

Although there is no U.S. federal law prohibiting germline modifications, both a federal appropriations rider and NIH policy apply to human embryonic research. The Dickey-Wicker Amendment, first included as a federal appropriations rider in 1996, states that “[n]one of the [federal] funds . . . may be used for—(1) the creation of a human embryo or embryos for research purposes; or (2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses.”¹⁴

Policy changes under the Obama administration also add to the regulatory landscape. In March 2009, President Obama issued an executive order removing federal funding restrictions for embryonic stem cell research put in place by previous administrations and tasked the NIH to develop guidance for such research. Subsequently, the April 2012 D.C. Circuit court decision in Sherley v. Sebelius clarified that the Dickey-Wicker Amendment was ambiguous as to the term “use,” leaving ample discretion for the NIH’s determination that federal funds could be dispersed for research that accessed discarded embryos but did not directly destroy those embryos.¹⁵ This remains the interpretation of the NIH and the White House.

However, the Obama administration has spoken out regarding germline alterations generally and gene editing specifically. The NIH director, Dr. Francis Collins, proclaimed in April 2015 that despite “an elegant new way of carrying out genome editing,” the NIH will not fund any use of gene-editing technologies in human embryos.¹⁶ The NIH Guidelines also specify that the RAC “will not at present entertain proposals for germ line alteration.”¹⁷ The White House issued a subsequent position on gene editing in May 2015, stating that the view of the administration is “that altering the human germline for clinical purposes is a line that should not be crossed at this time,” citing “serious and urgent questions.”¹⁸ Recent federal legislation prohibits use of federal funds by the FDA to “acknowledge receipt of a submission to initiate clinical trials of a drug or biological product” involving “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.”¹⁹ Commentators disagree as to whether that language applies to basic embryo research given the use of the term “heritable.”

State laws pertaining to human embryo research are also relevant to the regulation of germline gene editing. The National Conference of State Legislatures maintains a tally of states that have enacted laws that prohibit or restrict research on human embryos.²⁰ Even where federal law does not prohibit embryonic research, a particular state may have a more restrictive law. The application and scope of these laws to gene editing will be open to interpretation as the debate progresses.

One last related consideration for both somatic and germline gene editing is physician use. The clinical intervention approved by the HFEA using TALEN for acute lymphoblastic leukemia was targeted to a single patient as a last treatment resort. Thankfully, it was successful and the child is now in remission. Questions will arise as to the limits of the practice of medicine doctrine in the United States, which traditionally limits the FDA’s role in assessing and regulating physician off-label use and performance of therapeutic procedures. In the future, courts and juries may be called in to determine issues of medical negligence and products liability for use of gene editing when they become more mainstream.

Endnotes

1. See Martin Jinek et al., A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, 337 Sci. 816 (2012).

2. Id.

3. Sara Reardon, Gene-Editing Wave Hits Clinic, 527 Nature 146 (2015).

4. Sara Reardon, First CRISPR Clinical Trial Gets Green Light from US Panel, Nature (June 22, 2016), http://www.nature.com/news/first-crispr-clinical-trial-gets-green-light-from-us-panel-1.20137.

5. James Gallagher, “Designer Cells” Reverse One-Year-Old’s Cancer, BBC News (Nov. 5, 2015), http://www.bbc.com/news/health-34731498.

6. Alex Lash, Sean Parker to Fund CRISPR Trial, and Other Gene Edit Milestones, Exome (June 21, 2016), http://www.xconomy.com/national/2016/06/20/parker-reported-to-fund-crispr-trial-and-other-gene-edit-milestones/.

7. Int’l Soc’y for Stem Cell Research, Guidelines for Stem Cell Research and Clinical Translation 7 (2016) (Recommendation 2.1.3.3(a)); see also Insoo Hyun et al., Embryology Policy: Revisit the 14-Day Rule, 533 Nature 169 (2016).

8. Puping Liang et al., CRISPR/Cas9- Mediated Gene Editing in Human Tripronuclear Zygotes, 6 Protein & Cell 363 (2015); Xiangjin Kang et al., Introducing Precise Genetic Modifications into Human 3PN Embryos by CRISPR/Cas-Mediated Genome Editing, 33 J. Assisted Reprod. & Genetics 581 (2016).

9. Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products, 58 Fed. Reg. 53,248, 53,249 (Oct. 14, 1993).

10. Cellular and Gene Therapy Products, FDA, http://www.fda.gov/BiologicsBloodVaccines/ CellularGeneTherapyProducts/default.htm (last updated Oct. 20, 2015).

11. See, e.g., David Baltimore et al., A Prudent Path Forward for Genomic Engineering and Germline Gene Modification, 348 Sci. 36 (2015); Germline Editing: Time for Discussion, 21 Nature Med. 295 (2015); Edward Lanphier et al., Don’t Edit the Human Germ Line, 519 Nature 410 (2015).

12. Baltimore et al., supra note 11, at 37.

13. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules 100 (2016) [hereinafter NIH Guidelines].

14. Pub. L. No. 104-99, § 128, 110 Stat. 26, 34 (1996).

15. 689 F.3d 776 (D.C. Cir. 2012).

16. Francis S. Collins, Statement on NIH Funding of Research Using Gene-Editing Technologies in Human Embryos, Nat’l Insts. of Health (Apr. 28, 2015), https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using-gene-editing-technologies-human-embryos.

17. NIH Guidelines, supra note 13, at 100.

18. John P. Holdren, A Note on Genome Editing, White House Blog (May 26, 2015), https://www.whitehouse.gov/blog/2015/05/26/note-genome-editing.

19. Consolidated Appropriations Act, 2016, Pub. L. No. 114-113, § 749, 129 Stat. 2242, 2283 (2015).

20. Embryonic and Fetal Research Laws, Nat’l Conf. of St. Legislatures, http://www.ncsl.org/research/health/embryonic-and-fetal-research-laws.aspx (last updated Jan. 1, 2016).