L13: Gene Therapy Drug Development

Question 1

what are the two types of drugs

Answer 1

1. small molecules (chemicals) - most drugs are in this category
2. biologics (large biomolecules) proteins, genes, cell therapies, vaccines

Question 2

gene therapy in clinical trials –

what are the three types of drugs that are mostly being worked on?

what are the top three from the top two categories?

2010-2020

Answer 2

working on:
1. cancer
2. genetic disease
3. infections

cancer:
1. hematological cancer
2. GI cancer
3. Nervous system cancers

genetic diseases:
1. metabolic disease
2. eye disease
3. blood coagulation disorder

Question 3

describe the prominence of the three types of drugs being most worked on in each phase of clinical trials

Answer 3

phase 1:
1. cancer
2: genetics and infections

phase 2:
1. cancer
2. infections
3. genetics

phase 3:
1. genetic disease (long shot)
2. cancer
3. infections

phase 4: all very very low
1. genetic disease
2. infections / cancer

Question 4

how many approvals are there for gene therapy drugs by FDA in 2021?

Answer 4

very little
all other biologics = 318
gene therapy = 22 (HPC cord blood =8, cell therapy = 7, gene modified cell therapy = 5, gene therapy = 2)

Question 5

what was different in 2023 for approvals of gene therapies?

Answer 5

record breaking FDA approvals
- approval of 5 gene therapies
- approval of the first CRISPR-Cas9-edited therapy and a disease modifying Alzheimer’s drug

Question 6

List the gene therapy history of approvals from 2012, 2017, 2019, and 2023

Answer 6

• 2012 – lipoprotein lipase (rare disorder) deficiency, $1M, 31 patients treated worldwide
• 2017, gene therapy for hereditary eye disease
• 2019, gene therapy for Spinal muscular atrophy (SMA)
• 2023, 5 new gene therapy approvals including first gene editing (CRISPR) approval

Question 7

for gene therapies, comment on the:
- number of clinical trials
- how many genes do gene therapy like to work on
- what happens when gene therapies changes or adds a healthy copy of a gene
- what is one pro and two cons to the therapy

Answer 7

• Gene therapies are an emerging area of drug development
• Lots of clinical trials, only few approvals
  –> this is because there a lot of risks, such as causing cancer
• Gene therapies make the most sense when the disease mechanism involves a single gene – or if its for cancer, then the cancer is being driven by single gene
• Change or add a healthy copy of a gene –> to produce correct protein –> to improve patient health
• pro: a one and done therapy and it could cure you for the rest of your life
• cons: Possible side effects, costly

Question 8

Case study 1: gene therapy for eyes

targeted disease, process, gene, clinical trial, approval when

Answer 8

• Targeted disease: hereditary progressive vision loss (blindness)
• Process: Direct gene therapy to the cells of the retina (back of the eye where light sensing cells are) – Use a naturally-occurring viral vector to inject the DNA in the retina
• Gene: RPE65
• Clinical trial: 41 people (hard to find many people for this specific disease)
• When: Approved by FDA in 2017 (Luxturna)

Question 9

what is the cellular target for the case 1 gene therapy

Answer 9

RPE - retinal pigmented epithelial cells

Question 10

explain how AAV2 vectors are made and used in the eye (7)

Answer 10

• the retina is sprayed with saline solution to detatch from blood vessels
• the patients eye is injected at the retina
• this creates a genetically engineered virus gene-delivery system (AAV2 Vectors)
• the AAV2 vector is taken into the RPE cell via endosome
• the AAV2 vector binds to cell nucleus and releases contents which is a DNA circular episome (is not inserted into human chromosomes via splicing – instead a new DNA episome is created)
• the RPE65 protein is expressed, repairing damaged cells and helping vision
• the retina reattaches itself within a day

Question 11

who is the targeted population for the retinal gene therapy?

Answer 11

approved for children with inherited retinal disease, age 1 or order

Clinical trial data: 31 people

approved based on the fact that there was significant vision improvement that was maintained for > 1 year

Question 12

how did they measure efficacy for the retinal first case study

Answer 12

there was an obstacle course where the clinical trial participants needed to navigate it in low light levels to see if the gene therapy worked – indeed it did

Question 13

Case study 2: sickle cell disease (SCD)

what does normal red blood cell development look like?

Answer 13

in healthy individuals: the stem cells are in tissue’s bone marrow and mature into red blood cells which move into the blood steam

Question 14

who was treated of SCD in the first in human film and how

Answer 14

• Deidre Williams.
• Free of sickle cell disease due to stem cell transplant therapy from a donor relative.
  –> but what if you don’t need a donor – is this possible? yes with gene therapy

Question 15

refresher of how SCD works: describe how hemoglobin is made

Answer 15

there are two alleles in the hemoglobin B gene which encode for beta globin proteins (each protein variates a bit from the two proteins)
then the beta globin proteins combines with alpha globin to make the hemoglobin

alleles: variant. In human genetics, we inherit one allele from our father and one allele from our mother.

Question 16

refresher of how SCD works: how does sickle cell disease come to be (healthy vs sick)

Answer 16

healthy:
- 2 HBB genes code
- working beta globin combines with alpha globin to make hemoglobin
- this creates round flexible red blood cells to carry oxygen

sickle cell:
- 2 altered HBB genes
- altered beta globin sticks to one and other on the alpha globin
- created red blood cells which carry oxygen but fibres make them stiff and weirdly shaped

Question 17

who was the first patient for the approved gene therapy for SCD in 2023

Answer 17

Victoria Gray, Patient #1
Gene editing clinical trial for Sickle Cell Disease

Drug Approval Status: UK Nov 2023
USA Dec 2023

Question 18

is SCD rare or common disease?

what is the european definition of a rare disease and what are the stats of rare diseases (how many are classified as rare and how many do children account for, what percent of rare diseases are not approved for FDA treatment?)

Answer 18

its one of the most common rare diseases, globally impacts.

European definition: if it impacts fewer than 1 in 2000 its a rare disease– like SCD

7000 diseases are classified as rare, and children account for 50%

95% of rare diseases have no fda approved drug treatment !

Question 19

what is CRISPR and what are its 4 main functions?

Answer 19

CRISPR won the nobel prize in chemistry in 2020 for gene editing technology

it is essentially molecular scissors to edit human genes.

it works by either disrupting, deleting, or correcting/ inserting genes.

Question 20

Case study: CRISPR (gene editing) therapy for Sickle Cell Disease (Casgevy drug)

how does it work? (5)

Answer 20

how?
* Gene therapy outside of the patient
* Remove cells (blood stem cells) from patient
* Perform gene editing
* Deliver edited cells to patient
–> Edited stem cells expand in number inside the patient

Question 21

Case study: CRISPR (gene editing) therapy for Sickle Cell Disease (Casgevy drug)

challenge of every SCD patient having a different mutation – how do we achieve a “universal” gene editing therapy?

Answer 21

• Strategy: Gene editing is NOT of the hemoglobin B gene
• Instead, gene editing of a gene that controls fetal hemoglobin (how it matures in us)– the kind of hemoglobin we all have as babies
• Indirect approach to increase fetal hemoglobin

Question 22

explain hemoglobin biology: trends of alpha, beta, and gamma hemoglobin subunits before and after birth. what does CRISPR gene editing attempt to do?

Answer 22

Possible subunits of hemoglobin:
* Alpha
* Beta (healthy)
* Beta (sickled)
* Gamma (fetal)

• alpha hemoglobin is turned on 6 ish months before birth and stays on for the rest of your life
• gamma healthy hemoglobin turns off after birth (fetal hemoglobin)
• beta hemoglobin turns on after birth (this is the hemoglobin subunit that can either be healthy or sickled)

CRISPR gene therapy approach:
- in children, teenagers and adults, increase the expression of fetal hemoglobin by editing a gene that regulates fetal hemoglobin and keeps it on even after birth.

Question 23

explain the outcomes of the gene editing clinical trial for SCD

Answer 23

• 30 people in the clinical trial
• 29 people received edited cells with success
• No pain crises for over a year
  –> as determined by clinical signs/ symptoms
• Fetal hemoglobin elevated
  –> as indicated via biomarker
• Gene editing remains >70% = good thing because it is a permanent cure
  –> as indicated via biomarker

Johnny Lubin, clinical trial participant (age 15) – felt like he was getting superpowers

Question 24

what are the main concerns of CRISPR therapy to the public (2)

Answer 24

who will get access? its a one time treatment but it is very costly

Question 25

when is rare disease day and whats its purpose

Answer 25

on the 29th of feb (rare leap day)

raise awareness of rare diseases especially in the drug development conversation

Question 26

1. how many rare diseases are genetic (percent)?
2. how many genetic rare diseases start in childhood (percent)?
3. how many cancers are rare (blank in blank)?
4. the population of people with rare diseases equals that of (compare to country population)?

Answer 26

1. 72%
2. 70%
3. 1 in 5
4. the worlds 3rd largest country

Question 27

Compare small molecules to gene therapies? whats different? compare to biologics as well

Answer 27

see notes on onenote

should get at least 20 comparisons
development
trials
access
what the molecule is like
purity
etc.