Penyakit genetik

Sekitar 4000 penyakit manusia merupakan

penyakit keturunan/genetik
Mutasi gen merupakan faktor penyebab
yang perlu diperhatikan
Upaya yang lebih mungkin dengan
mencagah kemunculannya

Peta Genetic
pada kromosom
17

Penanganan Penyakit Genetik

Pembatasan substrat dalam diet
Pembuangan bahan yang berlebihan
Pemberian produk gen yang tidak
dihasilkan
Perbaikan dan penggantian dengan
operasi
Transplantasi organ/jaringan
Terapi gen

LanjutanPenanganan Penyakit Genetik

Pembatasan substrat dalam diet
Contoh : penderita Phenylketouria (PKU)
Caranya dengan membatasi masukan
phenylalanin dalam diet.
Phenilalanin merupakan asam amino yang
pada penderita PKU tidak dapat diubah
menjadi tirosin.
Akibatnya terjadi timbunan yang
menyebabkan ganggauan
syaraf.>retardasi mental

LanjutanPenanganan Penyakit Genetik

Pembuangan bahan yang berlebihan

Pemberian obat-abatan seperti Probenesid
untuk membuang asam urat pada
penderita penyakit Gout.
Perbaikan dan penggantian dengan operasi
Operasi bibir sumbing, celah langit-langit
atas, Polidaktili

LanjutanPenanganan Penyakit Genetik

Pemberian Produk Gen yang tidak

dihasilkan
Pemberian tiroid pada penyakit
hipotiroidosme (kreatinisme)

Transplantasi organ/jaringan
Transplantasi sumsum tulang pada
penderita Severe Combioned
Immunodeficiency disease (SCID)
TERAPI GEN
Sasaran : gen mutan
Strategi : mengambil gen mutan dan
menggantinya dengan gen normal
Gen replacement masih sulit

LanjutanTERAPI GEN
Gen corection memperbaiki gen mutan
tanpa menimbulkan perubahan genom
Gen augmentation menyisipkan,
penambahan gen yaitu
membangkitkan ekspresi gen mutan
dengan memasukan sequence gen
normal

Outline
Terapi gen pada penyakit keturunan

Genetic medicines: general considerations

Somatic stem cell therapy
Gene transfer
RNA-modification therapy

Terapi gen pada penyakit non keturunan

(acquired diseases)

1. Gene Therapy of
Hereditary Diseases
Genetic medicines:
terapi dipusatkan pada transfer genetik untuk
mengoreksi bagian genotip
Monogenic disorders = mutasi gen tunggal

Pre-genetic medicine era

Treatment of hereditary monogenic
diseases
Manipulasi metabolik
Penyisipan protein

Pre-genetic medicine era

Metabolic manipulation
Basic concept is to use dietary or small
molecule therapy to compensate for a
deranged biological process
Simplest form: diet modification (i.e.,
phenylalanine restriction to treat
phenylketonuria)

Pre-genetic medicine era

Protein augmentation
Simple concept: purify the missing protein
and return it to the patient
Most applicable to treating hereditary
disorders in which the deficient protein
functions in the extracellular milieu
Not effective for sites with difficult protein
diffusion (brain)

Genetic medicines in
hereditary disorders
1. Somatic stem cells (SSCs)
2. Gene transfer
3. RNA modification
4. Embryonic stem cells (ESCs)

Genetic medicines:
general considerations
to compensate for an autosomal recessive
disorder, 5-10% of normal gene expression
required to correct the phenotype
to compensate for autosomal dominant
disorders, the required levels are variable

Genetic medicines:
general considerations
genetic heterogeneity
stem cell therapy and gene transfer: specific
mutation is not as relevant
RNA-based strategies target specific
sequences and thus it is difficult to design
the therapy to fit all the mutations for some
disorders

Somatic stem cell therapy

Organ transplantation for a monogenic
disorder is the ultimate genetic
medicine (liver, kidney, lung, heart)
Stem cells are unspecialized cells with a
capacity for self-renewal and the ability to
differentiate into specialized cells

Embryonic stem cells:

derived from the inner cell mass of
embryos at the blastocyst stage,
pluripotent
Somatic stem cells (SSCs): derived from
various fetal and post-natal organs, at
minimum can differentiate into the cell
types found in the tissue in which they
reside

Stem cell therapy

Nature Reviews Genetics, 7, 261, 2006

Somatic stem cell therapy

Hematopoietic stem cell (HSC)
transplantation
bone marrow stem cell transplantation used
for >40 yrs
HSCs differentiate into all myleoid and
lymphoid blood lineages

HSC transplantation
Non-hematopoietic sources of SSCs
SSCs identified in brain, gut, heart, liver,
pancreas, skeletal muscle, and skin/hair

Approaches to Gene
Transfer
Two basic strategies of gene transfer for
an hereditary disorder:
Ex vivo gene transfer
In vivo gene transfer
Each have unique advantages and
disadvantages

Ex Vivo Gene Transfer

In this approach, the genes are
introduced into a cell outside the body
Remove cells from individual
Manipulate the cells in vitro
Re-infuse cells into the individual

Gene Transfer Vectors

relevant cells, traffic through the
cytoplasm and enter the nucleus

Gene Transfer Vectors

Viral vectors
DNA-based: adenovirus, adeno-associated
virus (AAV)
RNA-based: retrovirus, lentivirus

Non-viral vectors
dsDNA combined with liposomes

Gene Transfer Vectors:

Adenovirus
First vector used to treat an hereditary
disorder
DNA virus, natural affinity for airway
epithelium, cornea and gut

Nature Reviews Genetics, 7, 261, 2006

Gene Transfer Vectors:

Retrovirus
Mainly used for ex vivo strategies
because of their sensitivity to
complement activation and difficult
concentration to high titers
Most clinical studies transfer wild-type
gene to T-lymphocytes or to autologus
HSCs to correct hematological diseases

Gene Transfer Vectors:

Retrovirus
ADA-SCID is a good target for gene therapy
Well-defined location (HSCs or mature T
cells)
Patients with as little as 5% of normal ADA
activity are phenotypically normal
Genetically corrected cells have a selective
advantage
ADA-SCID: the first gene therapy using
retrovirus used to transduce mature T cells ex
vivo

Gene Transfer Vectors:

Lentivirus

Lentivirus vectors are retroviruses based on

HIV1
Can infect non-dividing cells (i.e. suitable for in
vivo strategies to tissues not suitable for
retrovirus: CNS, liver)
Integrate permanently into the genome of the
target cell (risk of insertional mutagenesis
neoplasm development)

Nature Reviews Genetics, 7, 261, 2006

Steps in Gene Therapy In Utero

Terapi genetika

TERAPI GENETIKA

Tahapan umum
1. Isolasi gen Mutan yang menimbulkan
penyakit
2. menentukan sel sasaran untuk dimasuki
gen
3. Menanamkan gen normal hasil rekayasa
ke dalam sel sasaran
4. Mengendalikan ekspresi gen yang berupa
produksi protein sesuai keperluan
Hingga saat ini terapi gen
masih dalam ranah gagasan teoritis,
perlu pengkajian lebih lanjut wallahualam