Creutzfeldt Jacob Disease Neurodegenerative Disorder Biology Essay


Several studies shows that PrPc is a glycoprotein that is anchored to the cell surface by GPI (GlycosylInositolPhasphatidyl) and is involved in the conformational conversion into PrPsc. Therefore, targeting conversion of PrPc into PrPsc may be therapeutic for the prion disease (Carmen Krammer).There are four areas identified as a therapeutic targets for the treatment of Creutzfeldt jacob disease in particular variant Creutzfeldt jacob disease (vCJD).

Lot of chemical compounds such as polyanionic compounds, polycationic compounds, amyloid binding compounds, tetra cyclic compounds were employed to reduce the PrPsc formation. These compounds can prolong the incubation periods of the disease (Suchiro sakaguchi).Anti prion chemical compounds have a limited effect on the disease due to these molecules unable to cross the blood brain barrier (BBB). Due to this limitation immunotherapeutics such as anti PrP antibodies were developed to treat the disease.

Mechanism of antibody mediated prion inactivation:

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In the seeding model (figure----), it was believed to be direct interaction between PrPSC template and PrPC results in the formation of infectious prions. Anti prion antibodies bind to the PrPC C-terminal part (residues 144-156) and inhibit the formation of PrPSC. Anti PrP antibodies specifically bind to the PrPC and its cellular receptors to bock or modify the interaction of PrPC with PrPSC. Peptides with amino acid sequence of PrP (106-141) inhibit the conversion in cell free system. β-breaker peptides ( Peptides with PrP 115-122) can reverse the convertion of PrPSC and decrease the β-sheet part of the PrPSC to make it more susceptible to proteolysis.

Figure 1. Mechanisms of antibody-mediated prion


Possible mechanism of prion inactivation by anti prion antibody. A) Conversion of PrPC (squares) to PrPSc (triangles) according to the seeding model is shown to occur at the plasma membrane and/or endocytic vesicles. B) Antibodies recognising PrPC and PrPSc (shown in thin line Y-shaped symbol) interfere with the PrPC-PrPSc interaction. C) Alternatively, antibody binding sequesters PrPC and prevents it

from contacting PrPSc. D) Other mechanism of PrPSc inhibition include specific binding of antibodies (shown in bold line Y-shaped symbol) against PrPSc (1), antibody interference with the binding of PrPC and its cellular receptor(s) (2), or the binding of monovalent antibody fragments to PrPC (3). For details see text

Anti PrP antibodies:

Recently anti PrP antibodies employed to treat the disease in addition to the chemical compounds. PrP specific antibody fragments can cure the chronically infected N2a cells (suehiro sakaguchi). Peretz et al treated the chronically infected N2a cells with D13, D18, R1, R2, R72 and E49. They showed that D13 and D18 can reduce the PrPSC levels in dose dependant manner. Anti PrP activity is independent to each other due to the broadly located PrP multiple sites such as D18, D12, R2 and R1 specifically recognizes residues in-between 132-156, 95-103, 225-231, 220-231.

Anti PrP antibodies



3F4, 13A5 and Polyclonnal antibody (W3)

109-112, 138-165, 219-232.

Disturbs the interaction between PrPC and PrPSC.

31C6, 110, 72 (McAb) and 44B1.

143-149, 59-65 and 83-89 in the octapeptide region.

PrPC internalisation.

SAF34, SAF61


Octapeptide region

3S9, 2H9 141-161 and 151-221 reduce PrPSC levels.

Anti LRP/LR antibodies therapy:

Laminin receptor (LRP/LR) is a PrPC cell surface receptor. It is directly interact between PrP residues 144-179 and it is involved in the PrPSC formation. Leucht et al showed that W3 (LRP/LR specific polyclonal antibody) competes with the recombinant PrP when binding to the LRP/LR. ScFv antibodies have developed in recent times against specific epitopes of PrPC. The epitope of LRP for S18 located inside of the extra cellular domain of LRP (272-280). PrPSC levels have been reduced (approximately 40% in spleen) when the prion infected mice treated with ScFv S18 when compared to the C9 and PBS as shown in the figure ____. It is clearly indicated that ScFv S18 reduces the PrPSC propagation by disrupting the interaction between PrP/LRP. However frequent high doses of ScFv S18 need to treat the disease due to the short half life of antibody.

Fig: Epitope mapping of ScFv s18. (a) Membranes encompassing the huLRP sequence were hybridized with S18. The sequence of the peptides detected and the amino acid positions are indicated. (b) Schematic representation of LRP. The following binding sites are indicated: direct binding site to PrP (aa 161-179) (Hundt et al., 2001), a suggested indirect HSPG-dependent binding domain for PrP (aa 180-285) (Hundt et al., 2001), scFvS18 recognizes the epitope aa 272-280.

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Fig: Spleen analysis of mice inoculated with prions after intraperitoneal treatment with PBS, scFvC9 or scFvS18. Each group consists of six animals. (a) Analysis of PrPSc levels (after PK digestion) in the spleen has been performed 90 days after scrapie inoculation by western blotting. Shown are the PrPSc levels of three mice of each group injected with PBS, C9 and S18, respectively. (b) Densitometric measurements of western blots from six spleens per group revealed a reduction of the PrPSc level by 40% in the scFv S18 treated group compared to the PBS treated group, for which the PrPSc level was set to 100%

Direct injection of Anti PrP antibodies into brain:

White et al showed that intraperitoneal injection of Two anti PrP antibodies such as ICSM18 and ICSM 35 protected the mice from RML prions peripherally but does not show effect in the brain tissue. This is probably because of inability of antibodies to cross the blood brain barrier (BBB). Direct infusion of 3S9 monoclonal antibody into the right ventricle of the prion infected mice results in reduces PrPSC levels after 8 weeks but does not show effect after 13 weeks (sakaguchi). Song et al showed no significant difference of prolongation or marginally prolong the survival times when the Chandler prion infected mice treated with 31C6. It is effective against chandler prion at 60, 90 and 120 days whereas no prolongation with 31C6 when the mice infected with Obihiro strain. One problem associated with the CNS delivery of anti PrP antibodies is toxicity. Cross linking between PrP and some specific antibodies (bivalent) promotes neuronal cell apoptosis.

Virus vector mediated gene delivery:

Antibodies are macromolecules that do not cross the blood brain barrier (BBB). Therefore, molecular size reduction (without reducing anti prion activity) is very beneficial for treatment such as monovalent single chain variable fragments (ScFv). Recently, it is reported that adeno associated virus vector is used to deliver the anti PrP ScFv into the central nervous system. Recombinant ScFv D18 has the ability to prolong the incubation periods of the disease. PrP specific ScFvs have unique binding properties that include ScFv 3.4, ScFv 6.4, ScFv 6.6 and ScFv D18. ScFv D18 has shown to be very effective to prolong the incubation periods when these antibodies are injected into the different parts of the brain, indicates that anti PrP ScFv inhibits the formation of PrPSC in the brain.

Figure: Central nervous system (CNS) expression of recombinant adeno-associated vector type 2 (rAAV2) single-chain fragment variable (scFv) delays onset of prion disease. (b) Rotarod latencies from mice administered rAAV2 scFv D18 demonstrate improved performance compared to the other groups; (c) Clinical rating data show that the onset of signs of disease was delayed in mice administered rAAV2 scFvD18. Maximal clinical rating score achieved immediately prior to animals reaching moribund status and sacrificed.

Role of blood brain barrier and the agents that can cross blood brain barrier:

Blood brain barrier separates the blood from the cerebrospinal fluid and it restricts the entry of macromolecules such as drugs into the brain except that are small and lipophillic. The main problem in the therapy of creutzfeldt Jacob disease is inability of macromolecules such as chemical compound and antibodies to cross the blood brain barrier. Non peptide agents capable of identify a specific form of protein or structure related to the neurological conditions such as prions in transmissible spongiform encephalopathy. Renee Wegrzyn developed a promising approach of using pyrene to deliver the therapeutic agents across the blood brain barrier. When the pyrene conjugated to the non peptide therapeutic agent, it increases the permeability of the non peptide therapeutic agent across the blood brain barrier. Renee Wegrzyn et al administered non peptide therapeutic agent along with the pyrene (conjugate) to the mice intranasally (10µl liquid with 0.1-2.0 mg/ml, interval period 30 min) and they found the presence of the conjugate in the brain of transgenic mice indicated that it can cross the blood brain barrier.