Class 5
Neurogenetic discoveries and therapeutic strategies
Treatment of a neurogenetic disease and genetic treatment of a neurological disease are
two separate matters!
- Genetic treatment: you use genes to treat it
o Genetic treatment can also help in other diseases
- Neurogenetic disease: gene defect
o There are di;erent ways to treat neurogenetic diseases
In theory:
- Identification of causal genes and genetic risk factors will allow better understanding
of disease and identification of possible targets for therapies.
- Gene therapy may o;er therapeutic opportunity for some monogenic disorders.
- Genetic studies may allow individual complex diseases to be subdivided into
subtypes that each require tailored therapy.
- Pharmacogenetics may be used to predict treatment response in individual patients.
o Maybe some individuals can metabolism a drug faster than other
Specific challenges to treating neurological diseases
In practice in neurological diseases:
- Limited understanding of the causes of many neurological diseases
o Why are brain cells dying? For many diseases we don’t know it
- Accurate translational models to predict response to treatment are limited in
neurological diseases.
- Biomarkers that are reliable predictors for the rate of progression in individual patients
are often lacking (new hope on neurofilament light chain)
o You need biomarkers that the treatment is working
o You need also that give you an outcome fast and not in a few years
o The biomarkers need to be reliable
o Neurofilament is promising
...and specific issues related to brain diseases:
- There is limited access to brain structures that are protected by physical barriers such
as the blood brain barrier -> specialized delivery methods required
- Brain is complex with multiple cell types
- Many neurodegenerative diseases start decades before clinical symptoms. become
visible -> too late for treatment?
Example of Alzheimer’s disease (AD)
- Dotted line = moment that someone gets the first symptoms
- Green = inflammation of the brain
- Blue and red = accumulation of tau and amyloid
- Yellow = cell loss
è How we are going to predict who is going to be sick -> need for good biomarkers
,Broad approaches to treating genetic neurological
diseases
1. Treating genetic deficiency (loss of something)
2. Treating the production of harmful e;ects (correcting developmental
malformation, or eliminating toxic RNA, protein or metabolite)
3. Treating the underlying pathology (usually not done by gene therapy)
Gene therapy. In the medicine field, gene therapy (also called human gene transfer) is the
therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease
Approach 1: Restoring a loss
- Augmentation therapy: means something is provided to the patient that
supplements a severely depleted, or missing, factor, thereby overcoming the
deficiency and restoring function.
o Give something that is missing
- Most suited for recessive disorders (where both alleles have lost their function). Even
a modest e;iciency in delivery (of healthy cells, genes, or proteins) to an a;ected
individual may allow e;ective treatment.
o Usually for recessive disorders -> even you if you can bring a little bit back is
enough
- Problematic for some dominant disorders caused by haploinsu;iciency when
mutated gene is dosage-sensitive (=> too little and too much cause disease).
- Possible treatment approaches:
o Small molecule drug
o Viral delivery of gene of interest
o Restore genetic deficit using antisense oligonucleotides (ASO)
§ Can eliminate things of upregulation of the gene
Approach 2: eliminating toxic RNA/protein
- In many neurodegenerative diseases mutations lead to the accumulation of amyloid-
like structures, which form aggregates that kill cells.
o Mutations can be directly in disease-aggregating protein or can indirectly lead to
aggregation of disease protein
, - Unstable expansions of short oligonucleotide repeats may lead to production of
harmful proteins and/or RNAs
- Possible treatment approaches:
o Small molecule drug
o Therapeutic monoclonal antibody
o Viral vector delivery shRNA
§ Degrade RNA that makes proteisn
o Antisense interference strategies (ASOs)
è Last two can be used for loss and gain of function but they are used in a
di;erent way
Approach 3: treating the underlying pathology
Tuberous sclerosis complex
- Autosomal dominant disorder characterized by benign (noncancerous) tumors in
many organs including the brain; these tumors can disrupt how organs function.
- Additional abnormalities of cell migration and function in the brain lead to seizures,
autism, and learning di;iculties.
- Caused by mutations in TSC1 and TSC2.
- The TSC1–TSC2 complex was found to be part of the mTORC1 growth signaling
pathway -> mutations disrupt complex leading to constitutive mTORC1 signaling.
- Known drugs Rapamycin and Everolimus, are e;ective inhibitors of mTOR, a major
subunit of the mTORC1 complex, and work to suppress cell growth.
- These drugs thus targets the underlying pathophysiology of TSC. Everolimus was FDA
approved in 2018 to treat TSC.
Requires in-depth knowledge on disease!
Overview gene therapy approaches
- CRISPR Cas9: editing the DNA of patients -> not really done in humans
- ASOs
- AAV
Neurogenetic discoveries and therapeutic strategies
Treatment of a neurogenetic disease and genetic treatment of a neurological disease are
two separate matters!
- Genetic treatment: you use genes to treat it
o Genetic treatment can also help in other diseases
- Neurogenetic disease: gene defect
o There are di;erent ways to treat neurogenetic diseases
In theory:
- Identification of causal genes and genetic risk factors will allow better understanding
of disease and identification of possible targets for therapies.
- Gene therapy may o;er therapeutic opportunity for some monogenic disorders.
- Genetic studies may allow individual complex diseases to be subdivided into
subtypes that each require tailored therapy.
- Pharmacogenetics may be used to predict treatment response in individual patients.
o Maybe some individuals can metabolism a drug faster than other
Specific challenges to treating neurological diseases
In practice in neurological diseases:
- Limited understanding of the causes of many neurological diseases
o Why are brain cells dying? For many diseases we don’t know it
- Accurate translational models to predict response to treatment are limited in
neurological diseases.
- Biomarkers that are reliable predictors for the rate of progression in individual patients
are often lacking (new hope on neurofilament light chain)
o You need biomarkers that the treatment is working
o You need also that give you an outcome fast and not in a few years
o The biomarkers need to be reliable
o Neurofilament is promising
...and specific issues related to brain diseases:
- There is limited access to brain structures that are protected by physical barriers such
as the blood brain barrier -> specialized delivery methods required
- Brain is complex with multiple cell types
- Many neurodegenerative diseases start decades before clinical symptoms. become
visible -> too late for treatment?
Example of Alzheimer’s disease (AD)
- Dotted line = moment that someone gets the first symptoms
- Green = inflammation of the brain
- Blue and red = accumulation of tau and amyloid
- Yellow = cell loss
è How we are going to predict who is going to be sick -> need for good biomarkers
,Broad approaches to treating genetic neurological
diseases
1. Treating genetic deficiency (loss of something)
2. Treating the production of harmful e;ects (correcting developmental
malformation, or eliminating toxic RNA, protein or metabolite)
3. Treating the underlying pathology (usually not done by gene therapy)
Gene therapy. In the medicine field, gene therapy (also called human gene transfer) is the
therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease
Approach 1: Restoring a loss
- Augmentation therapy: means something is provided to the patient that
supplements a severely depleted, or missing, factor, thereby overcoming the
deficiency and restoring function.
o Give something that is missing
- Most suited for recessive disorders (where both alleles have lost their function). Even
a modest e;iciency in delivery (of healthy cells, genes, or proteins) to an a;ected
individual may allow e;ective treatment.
o Usually for recessive disorders -> even you if you can bring a little bit back is
enough
- Problematic for some dominant disorders caused by haploinsu;iciency when
mutated gene is dosage-sensitive (=> too little and too much cause disease).
- Possible treatment approaches:
o Small molecule drug
o Viral delivery of gene of interest
o Restore genetic deficit using antisense oligonucleotides (ASO)
§ Can eliminate things of upregulation of the gene
Approach 2: eliminating toxic RNA/protein
- In many neurodegenerative diseases mutations lead to the accumulation of amyloid-
like structures, which form aggregates that kill cells.
o Mutations can be directly in disease-aggregating protein or can indirectly lead to
aggregation of disease protein
, - Unstable expansions of short oligonucleotide repeats may lead to production of
harmful proteins and/or RNAs
- Possible treatment approaches:
o Small molecule drug
o Therapeutic monoclonal antibody
o Viral vector delivery shRNA
§ Degrade RNA that makes proteisn
o Antisense interference strategies (ASOs)
è Last two can be used for loss and gain of function but they are used in a
di;erent way
Approach 3: treating the underlying pathology
Tuberous sclerosis complex
- Autosomal dominant disorder characterized by benign (noncancerous) tumors in
many organs including the brain; these tumors can disrupt how organs function.
- Additional abnormalities of cell migration and function in the brain lead to seizures,
autism, and learning di;iculties.
- Caused by mutations in TSC1 and TSC2.
- The TSC1–TSC2 complex was found to be part of the mTORC1 growth signaling
pathway -> mutations disrupt complex leading to constitutive mTORC1 signaling.
- Known drugs Rapamycin and Everolimus, are e;ective inhibitors of mTOR, a major
subunit of the mTORC1 complex, and work to suppress cell growth.
- These drugs thus targets the underlying pathophysiology of TSC. Everolimus was FDA
approved in 2018 to treat TSC.
Requires in-depth knowledge on disease!
Overview gene therapy approaches
- CRISPR Cas9: editing the DNA of patients -> not really done in humans
- ASOs
- AAV
