Lecture 5 - Regulations on Human Embryo Research and Bioethics of its Manipulation

phase 1 trials

phase 1 trials

investigate new drugs or treatments for safety, efficacy and dosage on healthy volunteers or patients

phase 2 trials

further evaluate safety, efficacy and toxicity of new drugs and treatments on patients afflicted with the targeted condition

phase 3 trials

definitively assess the efficacy of new drugs/treatments on large groups of patients in multi-center trials

• compares the new treatment with current standard of care

what control trial is used in phase 3 trials?

double-blind randomized trial in which both the patient and the doctor do not know if the patient received the treatment or placebo

bone marrow transplant (HSCs)

first stem cell therapy; now cord blood HSCs and mobilized peripheral blood HSCs are also commonly used

skin or corneal epithelium graft (holoclar treatment)

epidermal stem cells or limbal stem cells expanded ex vivo on a scaffold for treating burn damage

retinal pigment epithelium (age related blindness)

replacement of damaged retinal tissues for specific types of age related blindness

insulin secreting B cells (type 1 diabetes)

encapsulated endodermal progenitor cells that mature in vivo for treatment

skeletal muscle repair

satellite cells for treatment of Duchenne Muscular Dystrophy

multipotent stromal cells (MSCs)

in many clinical trials and mainly thought to function by modulation of the immune system and promotion of angiogenesis (stand-alone or cotransplantation)

cartilage repair

chondrocytes for treatment of cartilage defects in the knee

compassionate use program

operates outside of the legal frameworks required for clinical trials to be approved

expanded access programs

only for patients with life threatening diseases that can’t be adequately treated with approved therapies

stem cell tourism

unproven treatments that are advertised as miracle cures and uncertain how complications are handled because they lack sufficient background information on the nature of the cells

why do people go to the unauthorized stem cell clinics?

• desperation

• media hype

• low scientific literacy

advanced therapeutic products

anything that is not quite a drug that can be marketed to patients

• cell based and gene therapies are in this category

homologous use?

does it contribute to the same tissue type it came from?

minimal manipulation

generally means no laboratory manipulation including cell line and culture

systemic effect dependent on metabolic activity

if affects on the cells goes beyond the tissue target (influence on immunity or metabolism

CTO (cell tissue organ)

example is bone marrow transplantation when cells are taken directly from bone marrow, minimal processing and delivered straight into the patient

why is the view of cell based therapeutic products as drugs not suitable?

because of the individualized nature of patient specific cell therapies or gene editing therapies

arguments for cell based therapies to be outside of drug framework

• cells/tissues are not massed produced

• show biological variability

• can be tailored to each specific patient (share genetic background + immune compatible)

fibroblast cells

non homologous because they are not being delivered back to the dermis and not minimally manipulated but are put into the drug category but not a medical device cause it can be used to repair organic tissue that is deteriorated in the patient

myofibers vary by:

• genetic modification strategy

• iPSC differentiation

• myoblast differentiation

• dosage

assisted human reproduction act (2004)

comprehensive legal prohibition of the transfer of human stem cells into animal embryos, any manipulation of human embryos and the creation of embryos for research purposed

who does this act protect?

Canadians who can access or are born of assisted reproduction technologies like in vitro fertilization (IVF_

assisted human reproduction act exception

requires permission to conduct research on embryos that are no longer required for fertility treatments upon the full and informed consent of donors

mitochondrial replacement therapy (MTT)

mitochondrial genome has 37 genes from the mother and can have diseased mutations and in the UK people with high risk for passing on one of these mutations can undergo mitochondrial replacement

how does MTT work?

the diseased mitochondria is removed and the donor egg takes out its nuclear material then the empty donor egg get the nuclear material of the afflicted person

MRT social considerations

enucleated oocyte donor is making a genetic contribution ot the unborn child cause the mitochondria has its own genetic information so:

• is it a cure for a child that would otherwise be born with severe mitochondrial disease?, does the mtDNA contribute to the development of a healthy baby grant any parental rights

• creating a new genetically distinct child?, is it truly a therapy then cause the child cant give informed consent

mosaicism

a multicellular organism composed of genetically distinct cells as a result of a genetic mutation in some percentage of cells during development

questions regarding embryo gene editing

• safety/efficiency of CRISPER-Cas 9 editing

• unintended off target effects

• consequences of genetic mosaicism

CRISPER baby scandal

Dr Jiankui claimed to have transferred gene edited cells to a woman who gave birth to the first designer baby and there was no evidence of the gene modification being successful so he was fired, fined and sent to prison

CRISPER baby target gene modification

targeting CCR5 for HIV resistance