Genomics Final exam drugs

ex vivo gene therapy

Zynteglo

what disease does Zynteglo treat

B-thalassemia

Zynteglo MOA

hematopoietic stem cells are infected with a viral vector that contains a single amino acid switch (Thr/Gln) that now can produced functional hemoglobin

in vivo gene therapy examples

Luxturna and Zolgensma

what disease does Luxturna treat

inherited vision lost, RPE65 mutation

MOA of Luxturna

Recombinant adeno-associated virus of serotype 2(rAAV2) expressing a working copy of the RPE65 gene, intraocular injection

Zolgensma

gene therapy for SMA, inject a virus containing SMN cDNA

ASO

antisense oligonucleotides, modified RNA drug that is complementary to endogenous RNA

-siran drug ending

block message (siRNA)

-rsen drug ending

alter message (antisense)

what disease does Onpattro (patisiran) treat

hATTR amyloidosis, misfolded TTR protein and aggregation

RNA therapy

Onpattro (patisiran)

double stranded RNA, select C and U bases have 2-O-2 methyl nucleosides for stability

target of Onpattro (patisiran)

TTR mRNA

MOA of Onpattro (patisiran)

bind to TTR mRNA, RISC recognizes the TTR mRNA/patrisiran complex, TTR mRNA is cleaved preventing translation into a protein

Spinraza (nusinersen)

RNA therapy for SMA

target of Spinraza (nusinersen)

SMN2 primary transcript

MOA of Spinraza (nusinersen)

prevents exon 7 from being spliced out, SMN2 mRNA can be translated into protein

Risdiplam (Everysdi)

small molecule that treats SMA

MOA of Risdiplam (Everysdi)

prevents exon 7 skipping of the SMN message, daily dosing (not one and done)

Eteplirsen (exondys 51)

RNA therapy for MD

target of Eteplirsen (exondys 51)

dystrophin primary transcript (mRNA)

MOA of Eteplirsen (exondys 51)

splices out exon 51 with the stop mutation codon, creates a shorter dystrophan protein but it can be expressed

Cytokine therapy examples

fligrastim and pegfilgrastim

Pegfilgrastim

biobetter agent

a PEG molecule is added to Filgrastim

treats neutropenia, dose is once every chemo cycle

MOA of Pegfilgrastim

binds to the Granulocyte colony-stimulating factor receptor on hematopoietic cells in the bone marrow, increased neutrophil production and function

examples of enzyme replacement therapy

Alglucosidase alpha (Myozyme/Lumizyme) (1 st gen)

Avalglucosidase alpha-ngpt (Nexviazyme) (2nd gen)

Cipaglucosidase alfa-atga (Pombiliti) (3rd gen) + Opfolda®(Miglustat)

Myozyme

first generation of ERT for Pompe Disease

terminal sugars are not mannose

bind to receptors on the lysosome, get engulfed and can start breaking down glycogen

nexviazyme (avalglucosidase alpha-ngpt)

second generation of ERT for Pompe Disease

synthetic mannoses are added post-production

Pombiliti plus Opfolda (miglustat)

third generation of ERT for Pompe Disease

post-translational modification to produce high density mannose phosphate on the protein in the host cells

chimeric Mab that targets TNF-a

Infliximab (remicade)

recombinant human Mab that targets TNF-a

adalimumab (humira)

chimeric fusion receptor/antibody that targets TNF-a

Etanercept (Endrel)

humanized Fab that targets TNF-a

Certolizumumab (cimzia)

Certolizumumab

only Fab, no Fc

binds to TNF-A preventing it from reaching target cells causing inflammation

what is the benefit of Certolizumumab not having a Fc region

no ADCC, no extra inflammation

Zaltrap

recombinant, soluble VEGF receptor fused to an antibody Fc region

what does Zaltrap treat

metastatic colorectal cancer and VEGF growth factor over-expression

target of Zaltrap

VEGF ligands

what allows Zaltrap to be excluded from the membrane anchoring domain

alternative splicing, shorterned cDNA to exclude the part coding for the membrane portion of the VEGF receptor

Eylea (aflibercept)

MAb

Used to treat neovascular macular degeneration (AMD)

protein identical to Zaltrap but for ophthalmic dosing

Trastuzumab (Herceptin)

Mab

used to treat metastastic breast cancer (HER2 positive cancer)

what is the target of Trastuzumab (Herceptin)

HER2 receptor

binds to the base of the extracellular domain

Pertuzumab (Perjeta)

MAb

binds to the dimerization arm of HER2 receptor

KADCYLA (trastuzumab emtansine)

ADC

HER2 positive cancers

target of KADCYLA (trastuzumab emtansine)

HER2 receptor

MOA of KADCYLA (trastuzumab emtansine)

bind to HER2 receptor, get internalized and when the antibody gets degraded DM1 is released (small molecule) which will then inhibit mitosis

immunotherapy check point inhibitors

Pembrolizumab and Nivolumab

target of Pembrolizumab and Nivolumab

PD-1 receptor

Pembrolizumab and Nivolumab MOA

block cancer cells from binding to PD and now can be recognized by immune cells and attacked