Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2004-03-31
2004-11-16
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C514S002600, C530S300000, C530S324000, C530S403000
Reexamination Certificate
active
06818218
ABSTRACT:
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe,
TINS
16, 403-409 (1993); Hardy et al., WO 92/13069; Selkoe,
J. Neuropathol. Exp. Neurol
. 53, 438-447 (1994); Duff et al.,
Nature
373, 476477 (1995); Games et al.,
Nature
373, 523 (1995). Broadly speaking the disease falls into two categories: late onset, which occurs in old age (65+years) and early onset, which develops well before the senile period, i.e, between 35 and 60 years. In both types of disease, the pathology is the same but the &bgr;normalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 &mgr;m across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of tau protein consisting of two filaments twisted about each other in pairs.
The principal constituent of the plaques is a peptide termed A&bgr; or &bgr;-amyloid peptide. A&bgr; peptide is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer's disease. See, e.g., Goate et al.,
Nature
349, 704) (1991) (valine
717
to isoleucine); Chartier Harlan et al.
Nature
353, 844 (1991)) (valine
717
to glycine); Murrell et al.,
Science
254, 97 (1991) (valine
717
to phenylalanine); Mullan et al.,
Nature Genet
. 1, 345 (1992) (a double mutation changing lysine
595
-methionine
596
to asparagine
595
-leucine
59
). Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to A&bgr;, particularly processing of APP to increased amounts of the long form of A&bgr; (i.e., A&bgr;1-42 and A&bgr;1-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form A&bgr; (see Hardy,
TINS
20, 154 (1997)). These observations indicate that A&bgr;, and particularly its long form, is a causative element in Alzheimer's disease.
McMichael, EP 526,511, proposes administration of homeopathic dosages (less than or equal to 10
−2
mg/day) of A&bgr; to patients with preestablished AD. In a typical human with about 5 liters of plasma, even the upper limit of this dosage would be expected to generate a concentration of no more than 2 pg/ml. The normal concentration of A&bgr; in human plasma is typically in the range of 50-200 pg/ml (Seubert et al.,
Nature
359, 325-327 (1992)). Because EP 526,511's proposed dosage would barely alter the level of endogenous circulating A&bgr; and because EP 526,511 does not recommend use of an adjuvant, it seems implausible that any therapeutic benefit would result.
By contrast, the present invention is directed inter alia to treatment of Alzheimer's and other amyloidogenic diseases by administration of A&bgr; or other immunogen to a patient under conditions that generate a beneficial immune response in the patient. The invention thus fulfills a longstanding need for therapeutic regimes for preventing or ameliorating the neuropathology of Alzheimer's disease.
SUMMARY OF THE CLAIMED INVENTION
In one aspect, the invention provides methods of preventing or treating a disease characterized by amyloid deposition in a patient. Such methods entail inducing an immune response against a peptide component of an amyloid deposit in the patient Such induction can be active by administration of an immunogen or passive by administration of an antibody or an active fragment or derivative of the antibody. In some patients, the amyloid deposit is aggregated A&bgr; peptide and the disease is Alzheimer's disease. In some methods, the patient is asymptomatic. In some methods, the patient is under 50 years of age. In some methods, the patient has inherited risk factors indicating susceptibility to Alzheimer's disease. Such risk factors include variant alleles in presenilin gene PS1 or PS2 and variant forms of APP. In other methods, the patient has no known risk factors for Alzheimer's disease.
For treatment of patients suffering from Alzheimer's disease, one treatment regime entails administering a dose of A&bgr; peptide to the patient to induce the immune response. In some methods, the A&bgr; peptide is administered with an adjuvant that enhances the immune response to the A&bgr; peptide. In some methods, the adjuvant is alum. In some methods, the adjuvant is MPL. The dose of A&bgr; peptide administered to the patient is typically at least 1 or 10 &mgr;g, if administered with adjuvant, and at least 50 &mgr;g if administered without adjuvant. In some methods, the dose is at least 100 &mgr;g.
In some methods, the A&bgr; peptide is A&bgr;1-42. In some methods, the A&bgr; peptide is administered in aggregated form.
In other methods, the A&bgr; peptide is administered in dissociated form. In some methods, the therapeutic agent is an effective dose of a nucleic acid encoding A&bgr; or an active fragment or derivative thereof. The nucleic acid encoding A&bgr; or fragment thereof is expressed in the patient to produce A&bgr; or the active fragment thereof, which induces the immune response. In some such methods, the nucleic acid is administered through the skin, optionally via a patch. In some methods, a therapeutic agent is identified by screening a library of compounds to identify a compound reactive with antibodies to A&bgr;, and administering the compound to the patient to induce the immune response.
In some methods, the immune response is directed to aggregated A&bgr; peptide without being directed to dissociated A&bgr; peptide. For example, the immune response can comprise antibodies that bind to aggregated A&bgr; peptide without binding to dissociated A&bgr; peptide. In some methods, the immune response comprises T-cells that bind to A&bgr; complexed with MCH1 or MHCII on CD8 or CD4 cells. In other methods, the immune response is induced by administering an antibody to A&bgr; to the patient. In some methods, the immune response is induced by removing T-cells from the patient, contacting the T-cells with A&bgr; peptide under conditions in which the T-cells are primed, and replacing the T-cells in the patient.
The therapeutic agent is typically administered orally, intranasally, intradermally, subcutaneously, intramuscularly, topically or intravenously. In some methods, the patient is monitored followed administration to assess the immune response. If the monitoring indicates a reduction of the immune response over time, the patient can be given one or more further doses of the agent.
In another aspect, the invention provides pharmaceutical compositions comprising A&bgr; and an excipient suitable for oral and other routes of administration. The invention also provides pharmaceutical compositions comprising an agent effective to induce an immunogenic response against A&bgr; in a patient, and a pharmaceutically acceptable adjuvant. In some such compositions, the agent is A&bgr; or an active fragment thereof. In some compositions, the adjuvant comprises alum. In some compositions, the adjuvant comprises an oil-in-water emulsion. In some compositions, the A&bgr; or active fragment is a component of a polylactide polyglycolide copolymer (PLPG) or other particle. The invention further provides compositions comprising A&bgr; or an active fragment linked to a conjugate molecule that promotes delivery of A&bgr; to the bloodstream of a patient and/or promotes an immune response against A&bgr;. For example, the conjugate can serve to promote an immune response against A&bgr;. In some compositions, the conjugate is cholera toxin. In some compositions, the conjugate is an immunoglobulin. In some compositions, the conjugate is attenuated diphtheria toxin CRM 19
Neuralab Limited
Scheiner Laurie
Townsend and Townsend / and Crew LLP
LandOfFree
Prevention and treatment of amyloidogenic disease does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prevention and treatment of amyloidogenic disease, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prevention and treatment of amyloidogenic disease will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3315316