Lecture 1: Personalized/Precision Medicine

What is personalized medicine?

• Tailoring of medical treatment to the individual characteristics of each patient.

  • Specifically for you (one person).

• Examples: newborn screening, health tracking (Fitbit).

What is precision medicine?

• Tailoring of medical treatment to the characteristics of a specific group of people.

• Example: sickle cell anemia.

Tools of personalized/precision medicine

• Whole genome and exome sequencing.

• Transcriptome, Proteome, and Metabolome.

• Epigenome.

• Microbiome.

• Physiome and Exposome.

• Bioinformatics.

P4 Medicine

• Predictive.

• Preventative.

• Personalized.

• Participatory.

Sickle Cell Disease (SCD)

• Most common in African Americans.

• Affects people mostly in Africa, where malaria is endemic.

• High rate of mortality even with medical care (subtracts ~20 years off the lifespan).

• Caused by a single nucleotide change (GAG to GTG), which causes a specific amino acid swap (βGlu6Val).

• It is an autosomal recessive disorder.

• Sickle cell disease = HbSS.

• Sickle cell trait = HbSA.

Hemoglobin structure

• Hemoglobin is an oxygen carrier in red blood cells made of four subunits: two alpha (α) and two beta (β) polypeptide chains.

• Each subunit contains a globin (the protein chain) and a heme group (which holds iron).

• Specific amino acids at positions 6, 42, and 92 are highly conserved, meaning any change there is likely to cause functional problems.

Hemoglobin expression throughout life

• Before birth, humans produce Fetal Hemoglobin (HbF), which uses gamma (γ) chains. After birth, the body switches to Adult Hemoglobin (HbA), which uses beta (β) chains.

• HbF does not sickle in SCD.

• Because the sickle mutation is located on the beta (β) gene, infants are born healthy; symptoms only appear months later as HbF levels drop and the defective adult hemoglobin (HbS) takes over.

How the red blood cells become sickle-shaped

• Mutated hemoglobin (HbS) can still bind and transport oxygen normally.

• Under low oxygen conditions, the solubility of deoxygenated HbS drops significantly

  • It becomes only 1/5 as soluble as normal hemoglobin.

• Because of this low solubility, the HbS molecules clump together (aggregate) into a gelatinous network of stiff fibrous polymers.

• These stiff fibers are what physically push against the red blood cell membrane, causing the sickle shape.

Phenotypes of SCD

• Limit oxygen delivery to the body.

• Restricts blood flow.

• Severe pain and organ damage.

  • Vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs).

    • Painful episodes are caused when sickled red blood cells block blood flow.

Treatment of SCD

• Current:

  • Hydroxyurea: works by increasing the production of Fetal Hemoglobin (HbF), which prevents red blood cells from sickling and reduces painful vaso-occlusive crises.

  • Analgesics: pain relief.

  • Blood transfusion.

  • Allogeneic HSC transplantation:

    • Human stem cells that make blood cells.

    • Can cause Graft vs. Host disease:

      • When the donor’s immune cells view your body as “foreign” and begin to attack your organs.

    • Have to take immunodepressants or look for someone with a close MHC (major histocompatibility complex) for transplant (family member).

      • MHC: a set of proteins on the surface of your cells that helps your immune system distinguish between “self” and “foreign” invaders.

• Emerging treatment: gene therapy.

Gene therapy - Casgevy

• Approved for SCD patients who are 12 years or older.

• First FDA-approved therapy using CRISPR/Cas9.

  • CRISPR/Cas9: a gene-editing technology that acts like a pair of "molecular scissors" to precisely change existing DNA.

• Stem cells are removed from the patient, modified, and transplanted back into the patient.

• Increased production of HbF.

Gene therapy - Lyfgenia

• Approved for SCD patients who are 12 years or older.

• Uses a lentiviral vector for genetic modification.

  • Lentiviral vector: a modified, harmless virus used as a delivery vehicle to insert new genetic material into a patient's cells.

• Patient’s blood cells are removed and modified to produce HbA.

• Start to worry about cancer.

Caveats to gene therapy

• Most people with SCD live in Africa.

  • They will not have access to life-altering care.

• Long-term complications.

• Serious side effects.

• Very expensive ($2-3 million per patient), but lifetime medical costs of individuals living with SCD are also around this number.

  • It could be cost-effective.