Week 8.1 Gene Therapy and Bioethics: History, Technology, and Global Ethics
Introduction to Gene Therapy and Clinical Evolution
Conceptual Definition of Gene Therapy: Often described as a "one and done" approach, the promise of gene therapy is to provide a permanent cure for diseases by delivering genetic material directly to a patient. This can be done intravenously, directly into a tumor, or into the brain.
Historical Context: The concept was first proposed in the early 1970s by Ted Friedman, a professor at UC San Diego. At the time, the necessary technology was non-existent.
Technological Milestones: The field has progressed through several critical discoveries:
DNA structure (1950s).
First restriction enzymes (1970s).
Polymerase Chain Reaction (PCR) development.
Viral vectors and synthetic delivery methods.
Anecdote on PCR Evolution:
Early PCR required adding enzymes 30 times for 30 cycles because the enzymes were not thermostable (isolated from aquatic animals and destroyed by heat).
Scientists had to place a drop of oil on top of each tube to prevent evaporation and boiling of the solution onto the lid.
Modern PCR uses thermostable, high-fidelity enzymes and machines with heated lids, eliminating the need for oil and manual enzyme addition, ensuring the amplicon is a match to the original sequence.
Bioethical Frameworks in Biomedical Research
The Jesse Gelsinger Case (1999):
Patient: 18-year-old Jesse Gelsinger who suffered from Ornithine Transcarbamylase (OTC) deficiency.
The Disorder: An abnormality in the urea cycle, which metabolizes nitrogen. In humans, nitrogen is converted into ammonia, which is toxic and causes brain injury or death. The body normally converts toxic ammonia to urea through the urea cycle for excretion in urine.
Clinical Presentation: Jesse had a milder, late-onset form with some enzyme function. Neonatal onset patients usually die within days if the ammonia is not cleared, often suffering permanent brain injury.
The Trial: Jesse Gelsinger volunteered to help infants with more severe forms. He was administered an adenoviral vector carrying the therapeutic gene intravenously.
Outcome: He died on September 17, 1999, from a massive immune response. He was the first person publicly identified as having died from gene therapy for a monogenic disorder.
Historical Protective Codes:
Nuremberg Code: Born from the post-WWII trials; emphasized voluntary research, informed consent, and ensuring benefits outweigh risks.
Declaration of Helsinki: Mandated that all human research be approved by an Institutional Review Board (IRB) to protect patient privacy and safety.
National Research Act (1974): Established a commission for protecting human subjects.
Belmont Report: Defined ethical principles including informed consent, assessment of risks, respect for persons, and beneficence.
Issues in the Gelsinger Case:
Informed Consent: Questions remains regarding whether Jesse's family was told that three monkeys had died at the same dose he received.
Conflicts of Interest: Dr. James Wilson (University of Pennsylvania) held stock in Genovo, a company involved in the trial. It is now a rule that researchers with more than in financial interest cannot obtain informed consent or perform clinical management in a trial.
Regulatory Impact: This death caused the NIH and FDA to shut down all gene therapy trials in the US to investigate safety protocols.
Viral Vector Systems and Engineering
General Principle: Viruses are modified to be replication incompetent, meaning they cannot multiply inside the patient. They act as delivery vehicles for cDNA (messenger RNA converted to DNA).
Adenovirus:
Origin: One of three viruses causing the common cold.
Advantages: High transduction efficiency (especially in the liver), high gene expression, and a large genome capacity of approximately .
Disadvantages: Transient expression (it goes away), ubiquitous uptake (goes everywhere), and high pathogenicity (as seen in Jesse Gelsinger).
Retrovirus (including Lentivirus):
Mechanism: An RNA virus that integrates into genomic DNA, providing permanent expression in daughter cells.
Disadvantages: Only infects dividing cells, can be inactivated by the complement cascade in the bloodstream, and carries a risk of random integration.
The France Trial Exception: In an ex-vivo trial for X-linked sked (Severe Combined Immunodeficiency), boys were cured but two developed a leukemia-like syndrome. The retrovirus integrated near a T-cell oncogene called Elmo 2, activating a proto-oncogene and causing cancer.
Adeno-Associated Virus (AAV):
Origin: Member of the parvovirus family.
Advantages: No known pathogenicity in humans, infects both dividing and non-dividing cells, and has various serotypes (strains) that target specific tissues (cellular tropism) like the heart, brain, or lungs.
Disadvantages: Small genome capacity of only . To fit large genes like Hemophilia A ( cDNA) or Duchenne Muscular Dystrophy (DMD), researchers must remove non-essential sequences.
Vector Components:
Inverted Terminal Repeats (ITR): Specifically at the five prime and three prime ends.
Promoters: Regulatory elements used for tissue specificity (e.g., an albumin promoter limits expression to the liver).
Polyadenylation Signal: At the end to stabilize the RNA.
Gene Therapy Delivery Methods
Ex Vivo: Removing cells (like stem cells), treating them in a dish, and returning them to the patient. Example: Sickle cell disease (modifying CD 34 positive cells).
In Situ: Injecting the vector directly into a specific organ or tissue. Examples: Cystic fibrosis (via trachea), head and neck cancer tumors, or muscular dystrophy (injected into leg blood vessels).
In Vivo: Delivering the vector directly into the bloodstream to go to an organ like the liver. Example: Hemophilia A.
Commercial Realities and Drug Pricing
Ethical Concerns Over Pricing:
The price often goes to pharmaceutical manufacturers and involves Research and Development (R&D) costs.
Developing economies (e.g., Brazil) may receive slightly reduced prices (e.g., ), but it remains inaccessible for many.
Commercial failure: glide era (the first gene therapy approved worldwide) was withdrawn in 2018 because only one person received the drug commercially outside of clinical trials. Maintaining regulatory paperwork for stable drugs in freezers can cost annually.
Modern Ethical Challenges and Case Studies
The Casita Case (Recent):
A child with a genetic seizure disorder died from cerebral edema (brain swelling) two days after receiving a gene therapy (cap 002) designed to cross the blood-brain barrier.
The company, Casita, initially refused to disclose the receptor targeted or the cause of death.
It was later revealed the virus targeted Adam 15, a protein involved in cell adhesion.
Researchers like Benjamin Dairyman (Harvard/Broad Institute) argued the field lost 8 months of progress because Casita did not share this information, which could have helped other scientists ensure the safety of their own brain-targeted therapies.
Advocacy and Awareness:
Mr. Beast Games: Randy (Jeff Alan) won a prize to bring awareness to Creatine Transporter Deficiency (a disorder the speaker works on) and other rare disorders.
The Michael J. Fox Foundation: Has raised for Parkinson's disease research.
The Financial Barrier: While technology exists, funding for "ultra-rare" disorders (which can cost \10\text{ to }\ to get into clinical trials) is a major hurdle for academic labs.
Questions & Discussion
Question (Student): Where does the money ( per dose) go, and why is it so expensive if the actual biological material doesn't cost that much?
Response: The money goes to the pharmaceutical companies. They cite R&D costs and profit margins. It's often viewed as greed within the medical community. These disorders destroy families; the burden of care often falls on mothers, leading to high divorce rates and secondary stress for siblings.
Question (Student): Why do companies offer coupons if the drugs are so expensive?
Response: It may be to manage bad press or to help specific patient communities. In the US, single-payer systems (like the VA) have lower administrative costs (which account for about one-third of US health care spending), but private companies are driven by different economic incentives.