Preventing, Treating or Arresting Alzheimer's, Stroke, Cardiovascular and other Amyloid Related Diseases

Abstract

This invention provides systems and methods for arresting, treating and/or preventing diseases caused by amyloid deposits of proteins. This invention teaches procedures and therapeutic compositions for controlling amyloids and related plaque deposits. This invention is applicable to common diseases including, but not limited to: Alzheimer's, cardiovascular, stroke, arterial sclerosis, etc. By addressing plaque development at the earliest stages involving protein-protein interaction, plaque growth is decreased or eliminated and the balance of plaque deposition/management is switched to favor the body's natural aberrant protein removal mechanisms. The invention also simple provides procedures and/or kits for effective analysis to achieve earliest detection. Analysis may be undertaken in a clinical setting, but the present invention provides systems and methods for obtaining the relevant information in person by the patient or by an associate with no clinical training required.

Claims

1. A method for treating amyloid deposit disease comprising: delivering at least one glutathione support compound to a patient presenting with or presenting with at least one risk element of amyloid disease.

2. The method of claim 1 wherein said at least one risk element comprises a mutated cystatin C.

3. The method of claim 2 wherein said mutated cystatin C comprises a L68Q cystatin C.

4. The method of claim 1 wherein said glutathione support compound comprises an antioxidant.

5. The method of claim 1 wherein said at least one glutathione support compound comprises at least one substance or prosubstance that binds to and inhibits activity of cystatin C.

6. The method of claim 1 wherein said at least one glutathione support compound comprises at least one active compound selected from the group consisting of: selenium, n-acetylcysteine, S-adenosylmethionine and an ionophore.

7. The method of claim 5 wherein said at least one substance or prosubstance that binds to and inhibits activity of cystatin C comprises at least one cysteine protease molecule or derivative that binds or becomes capable of binding cystatin C.

8. The method of claim 7 wherein said substance or prosubstance comprises at least one member of a superfamily selected from the group consisting of: CA, CD, CE, CF, CL, CM, CN, CO, CP, PA, PB, PC, PD, PE and biosimilars and derivatives thereof.

9. The method of claim 8 wherein said substance or prosubstance comprises at least one member of a family selected from the group consisting of: C7, C8, C21, C23, C27, C36, C42, C53, C75 and biosimilars and derivatives thereof.

10. The method of claim 8 wherein said substance or prosubstance comprises at least one member of a family selected from the group consisting of: C1, C2, C3,C4,C5, C6, C9, C10, C11, C12, C13, C14, C15, C16, C18, C19, C25, C26, C28, C30, C31, C32, C33, C37, C39, C40, C44,C45, C46, C47, C48, C50, C51, C54, C55, C56, C57, C58, C59, C62, C63, C64, C65, C66, C67, C69, C70, C71, C74, C76, C78, C79, C80, C83, C84, C85, C86,C87, C89, C93, C95,C96, C97, C98, C99, C101 and P1 and biosimilars and derivatives thereof.

11. The method of claim 1, wherein said at least one glutathione support compound is delivered as a prodrug.

12. The method of claim 1, comprising delivering at least one anti-oxidant compound.

13. The method of claim 1 comprising at least one cysteine protease.

14. The method of claim 13 wherein said at least one cysteine protease comprises a lysosomal cysteine protease.

15. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from a virus.

16. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from a plant.

17. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from an archaebacterium.

18. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from a fungus.

19. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from an animal.

20. The method of claim 13 wherein said at least one cysteine protease molecule or derivative engineered to bind and to inhibit cystatin C is derived from a bacterium.

21. The method of claim 1 further comprising monitoring said patient with at least one bioassay capable of determining amyloid deposit presence.

22. The method of claim 21 wherein said at least one bioassay precedes said delivering.

23. The method of claim 21 wherein said at least one bioassay follows said delivering.

24. The method of claim 1 comprising a plurality of said delivering events.

25. The method of claim 21 comprising a plurality of said monitoring events.

26. The method of claim 25 wherein at least one of said monitoring events is input into an algorithm, said algorithm designed to output a suggestion selected from the group consisting of: at least one glutathione support compound, a dose relating to at least one glutathione support compound, a rate of delivering relating to at least one glutathione support compound and a route for said delivering relating to at least one glutathione support compound.

27. The method of claim 25 wherein at least two of said plurality of said monitoring events are separated by a time interval spanning at least about seven days.

28. The method of claim 25 wherein at least two of said plurality of said monitoring events are separated by a time interval spanning at least about two weeks.

29. The method of claim 27 wherein said at least about seven days comprises at least about 30 days.

30. The method of claim 27 wherein said at least about seven days comprises at least about 45 days.

31. The method of claim 27 wherein said at least about seven days comprises at least about 60 days.

32. The method of claim 27 wherein said at least about seven days comprises at least about 90 days.

33. The method of claim 27 wherein said at least about seven days comprises at least about 120 days.

34. The method of claim 27 wherein said at least about seven days comprises at least about 180 days.

35. The method of claim 27 wherein said at least about seven days comprises at least about 360 days.

36. The method of claim 21 wherein said monitoring comprises performance monitoring.

37. The method of claim 21 wherein said monitoring comprises imaging.

38. The method of claim 21 wherein said monitoring comprises obtaining a biosample from said patient.

39. The method of claim 38 wherein said obtaining is through remote delivery from said patient.

40. The method of claim 39 wherein said delivery is through a form of posting.

41. The method of claim 38 wherein said monitoring comprises analysis of said biosample at the site of collection.

42. The method of claim 38 wherein said monitoring produces a reading electronically delivered to at least one recipient selected from the group consisting of: said patient, a clinician, a pharmacist, a counselor and a device permitted by said patient.

43. The method of claim 38 wherein said biosample is assayed for amyloid deposit presence.

44. The method of claim 38 wherein presence of cystatin C protein or fragment thereof is monitored in said biosample.

45. The method of claim 44 wherein content of cystatin C or fragment thereof is quantified.

46. The method of claim 38 wherein said biosample comprises an integumentary biosample.

47. The method of claim 46 wherein said integumentary biosample, comprises a skin biosample.

48. The method of claim 46 wherein said integumentary biosample, comprises a buccal biosample.

49. The method of claim 38 wherein said biosample comprises a mucus biosample.

50. The method of claim 38 wherein said biosample comprises a blood biosample.

51. The method of claim 38 wherein said biosample comprises a urinary biosample.

52. The method of claim 38 wherein said biosample comprises a stool biosample.

53. The method of claim 38 wherein said biosample comprises a muscle biosample.

54. The method of claim 1 wherein said at least one glutathione support compound comprises a sulfur containing compound selected from the group consisting of: sulfhydryls, thioethers, thioacetals, thioamino acids, thioproteins and thioesters.

55. The method of claim 6 wherein said at least one glutathione support compound comprises n-acetylcysteine.

56. The method of claim 55 wherein delivery of n-acetylcysteine comprises one or a plurality of delivery events wherein an amount of n-acetylcysteine delivered is in accordance with the body mass of said patient.

57. The method of claim 56 wherein the delivery of n-acetylcysteine ranges from about 2 mg/kg to about 1400 mg/kg over a one to three day timespan.

58. The method of claim 57 wherein a delivered dose is selected from the group consisting of about: 2 mg/kg, 4 mg/kg, 8 mg/kg, 10 mg/kg, 16 mg/kg, 20 mg.kg, 32 mg/kg, 40 mg/kg, 50 mg/kg, 64 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 200 mg/kg and 250 mg/kg.

59. The method of claim 24 wherein said plurality of delivering events comprises at least two said events selected from the group of time intervals consisting of about: 1 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, 2 days, 3 days and 5 days.

60. The method of claim 55 wherein a plurality of delivering events comprises at least two said events selected from the group of time intervals consisting of about: 1 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, 2 days, 3 days and 5 days.

61. The method of claim 55 wherein said patient is delivered a treatment dose selected from the group consisting of about: 100, 200, 500, 600, 750, 800, 100, 1200, 1400 and 1500 mg/day.

62. The method of claim 1 wherein said at least one glutathione support compound comprises a sulfur containing compound selected from the group consisting of: 2-mercaptoethanol, cysteine, glutathione, thioalkylates, furan-2-ylmethanethiol, grapefruit mercaptan, 2-propene-1-thiol, thioredoxin, glutaredoxin, thiazolidinediones and methionine.

63. The method of claim 1 further comprising delivering to said patient at least one compound selected from the group consisting of: B1, B2, B6, B9, B12, and: selenium, magnesium, iron, and zinc metal complexes or ions.

64. The method of claim 1 further comprising delivering to said patient at least one compound selected from the group consisting of: cinnamon, cumin, tumeric, ginger, cardamom, and other cannabinoid compounds having similar metabolic activities.

65. The method of claim 1 further comprising delivering to said patient at least one compound selected from the group consisting of: interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, cytokine receptors for IL-1, tumor necrosis factor-, and IL-18 and derivatives and biosimilars thereof.

66. The method of claim 1 further comprising delivering to said patient at least one compound selected from the group consisting of: sulinac, sulindac sulfide, pravadoline, naproxen, naproxen sodium salt, meclofenamate sodium, ibupropfen, S-ibuprofen, piroxicam, ketoprofen, S-ketoprofen, R-ibuprofen, Ebselen, ETYA, diclofenac, diclofenac diethylamine, flurbiprofen, fexofenadine, Pterostilbene, Pterocarpus marsupium, 9,12-octadecadiynoic acid, Ketorolac (tromethamine salt), NO-indomethacin, S-flurbiprofen, sedanolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac ibuprofen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)1H-indole-2,3-dione, aceclofenac, acetylsalicylic acid-d4, S-ibuprofen lysinate, loxoprofen, CAY10589, ZLJ-6, isoicam, dipyrone, YS121, and MEG (mercaptoethylguanidine).

67. A medicament for managing amyloid deposits in an animal, said medicament comprising a glutathione support compound and an anti-inflammatory compound.

68. The medicament of claim 67 wherein said anti-inflammatory compound is selected from the group consisting of: a cytokine active substance, biosimilars and derivatives thereof and a synthetic compound that inhibits inflammation.

69. The medicament of claim 67 wherein said anti-inflammatory compound is selected from the group consisting of: interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, cytokine receptors for IL-1, tumor necrosis factor-, IL-18 and derivatives and biosimilars thereof, sulinac, sulindac sulfide, pravadoline, naproxen, naproxen sodium salt, meclofenamate sodium, ibupropfen, S-ibuprofen, piroxicam, ketoprofen, S-ketoprofen, R-ibuprofen, Ebselen, ETYA, diclofenac, diclofenac diethylamine, flurbiprofen, fexofenadine, Pterostilbene, Pterocarpus marsupium, 9,12-octadecadiynoic acid, Ketorolac (tromethamine salt), NO-indomethacin, S-flurbiprofen, sedanolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac ibuprofen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)1H-indole-2,3-dione, aceclofenac, acetylsalicylic acid-d4, S-ibuprofen lysinate, loxoprofen, CAY10589, ZLJ-6, isoicam, dipyrone, YS121, and MEG (mercaptoethylguanidine).

70. The medicament of claim 67 wherein said glutathione support compound is selected from the group consisting of: selenium, n-acetylcysteine, S-adenosylmethionine, 2-mercaptoethanol, cysteine, glutathione, thioalkylates, furan-2-ylmethanethiol, grapefruit mercaptan, 2-propene-1-thiol, thioredoxin, glutaredoxin, thiazolidinediones and methionine.

71. The medicament of claim 67 wherein said glutathione support compound is selected from the group consisting of: member of a superfamily selected from the group consisting of: CA, CD, CE, CF, CL, CM, CN, CO, CP, PA, PB, PC, PD, PE and biosimilars and derivatives thereof.

72. The medicament of claim 67 wherein said glutathione support compound comprises at least one member of a family selected from the group consisting of: C1, C2, C3, C4, C5, C6, C9, C10, C11, C12, C13, C14, C15, C16, C18, C19, C25, C26, C28, C30, C31, C32, C33, C37, C39, C40, C44, C45, C46, C47, C48, C50, C51, C54, C55, C56, C57, C58, C59, C62, C63, C64, C65, C66, C67, C69, C70, C71, C74, C76, C78, C79, C80, C83, C84, C85, C86,C87, C89, C93, C95, C96, C97, C98, C99, C101, C7, C8, C21, C23, C27, C36, C42, C53, C75, P1 and biosimilars and derivatives thereof.

73. The medicament of claim 69 comprising at let one compound selected from the group consisting of: interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, cytokine receptors for IL-1, tumor necrosis factor-, IL-18 and derivatives and biosimilars thereof and at least one compound selected from the group consisting of: sulinac, sulindac sulfide, pravadoline, naproxen, naproxen sodium salt, meclofenamate sodium, ibupropfen, S-ibuprofen, piroxicam, ketoprofen, S-ketoprofen, R-ibuprofen, Ebselen, ETYA, diclofenac, diclofenac diethylamine, flurbiprofen, fexofenadine, Pterostilbene, Pterocarpus marsupium, 9,12-octadecadiynoic acid, Ketorolac (tromethamine salt), NO-indomethacin, S-flurbiprofen, sedanolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac ibuprofen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)1H-indole-2,3-dione, aceclofenac, acetylsalicylic acid-d4, S-ibuprofen lysinate, loxoprofen, CAY10589, ZLJ-6, isoicam, dipyrone, YS121, and MEG (mercaptoethylguanidine).

74. The medicament of claim 67 comprising at least one supplement selected from the group consisting of: B1, B2, B6, B9, B12, and: selenium, magnesium, iron, and zinc metal complexes or ions.

75. The medicament of claim 67 comprising at least one supplement selected from the group consisting of: cinnamon, cumin, tumeric, ginger, cardamom, and other cannabinoid compounds having similar metabolic activities.

Description

ILLUSTRATIVE EXAMPLES

[0046] There are several hundred patients in Iceland who suffer from HCCAA (i.e., suffering major strokes in their early 20s) and they all descend from a founder mutation from the early 1500. The inventors have performed RNAseq on 30 subjects from 3 multiplex families and have shown that genes involved in coronary disease, stroke and atherosclerosis are upregulated in mutation carriers of cystatin C. To date there is no therapy available for these patients. Accordingly, intervention that has a potential to delay or reverse the disease process would be readily approved by the Icelandic Medicinal Agency.

[0047] Amyloid fiber dimerization is a critical step in the amyloid deposition process into small-medium sized brain arteries. In cell based assays, we have shown that both the wild type and mutated proteins are expressed and that expression of the mutated protein dimerizes, a process that can be inhibited. Thus, drugs that test as effective in an assay as blocking dimerization of the amyloid fibers are anticipated to be effective in preventing amyloid deposition and therefore to halt or reverse progression of the disease process. Such, selecting, analyzing, improving and reselecting, when successful, should, present increasingly effective therapies for HCCAA, and if robustly successful, e.g., in accessing the central nervous system tissue side of the blood brain barrier will become an effective therapy for AD.

[0048] In several embodiments biomolecules are elements of effective therapeutics. The natural biomolecules, when described or named are intended as shorthand expression to include, for example, a complete transcribed gene translated into a protein, splice variants, autolytic and other fragments, precursors, synthetic molecules including those comprising fragments includingwhen effectivefragments comprising D-amino acids and/or amino acids not having a natural codon in mammals, fragments or full length molecules comprised in a larger molecule, biosimilar substances, dimers and multimers of the original active ingredient with the active site accessible or accessible following normal metabolic processing, and prodrugs. Derivatives and prosubstances include but are not limited to: substances that metabolize to form the base substance, metabolites of the base substance maintaining at least one desired bioactivity, salt, hydroxides, hydroxylated, esters, etc. thereof.

[0049] This example of the invention commences with: [0050] a) Selecting a substance capable of binding a cystatin C. Several such substances are known in the art including: i) papain and other members of the cysteine protease family such as falcipains; ii) glutathione, important for scavenging lipid hydroperoxides and reducing hydrogen peroxide iii) cathepsin B, a lysosomal cysteine protease; iv) selenium, a semi-metal atom in the oxygen sulfur family, with known toxicity but also important biologically in anti-oxidation though its presence in glutathione peroxidase; and v) monensin, an ionophoric anti-biotic that can facilitate passage of ions across cell membranes. Other substances with similar activity to the above might be selected depending on accessibility and/or additional substances might be conceived, synthesized or otherwise obtained for testing. Engineered analogues or chemical mimics of such biologics, including fragment and biosimilars and those engineered to no longer have the original bioactivity, but still retaining an available cystatin C binding site are included in this grouping. [0051] b) Administering said substance to a cell culture or a cell culture extract preparation. Specific reaction conditions may be assessed here. Cell extract or synthetic cytoplasm like preparations might be used. For simplicity, to minimize screening costs, and/or to a balanced salt solution could be used as a viable substitute. Cells in culture are common vehicles for carrying out these type assessments. Monitoring results of said administering. Generally monitoring these types of results will require a control for comparison. The control may be a similar pharmaceutical substance, for example, an optical isomer. It may be a series of concentrations as common in making dose response curves. Dimerization itself can be monitored, alternatively, a surrogate or easily measured result with high correlation to dimerization can be measured. [0052] c) Repeating a) through c) at least one time. Repeating may be coincidental (parallel) or repeated monitoring may be in subsequent experimental runs (serial). The repeating may also have an element of a control. Multiple results under different conditions, for example different concentrations or substances, will assist refinement of processes and choosing an optimal substance for therapeutic use. [0053] d) Comparing results obtained in d). The plural result sets under different conditions facilitate selection, which may involve one or more of several factors, such as cost, efficacy, availability, durability (shelf-life), toxicity, partitioning to particular cells, tissues or organs, ability to cross membranes, ability to survive digestion, ability to cross the blood-brain barrier, customer acceptance, side effects, required dose, required number or frequency of dosing, regulatory body approval or clearance, reliability of supply chains, storage requirements, shipping restrictions, etc. [0054] e) Selecting a preferred substance from results e). Based on factors mentioned above or other factors considered relevant to the patient or patient pool, a substance is selected as a preferred substance. A plurality of preferred substances may be selected if a plurality of conditions or patient types is considered. [0055] f) And, providing said preferred substance for human use. The desire of the inventor is to improve the health, lifespan, or quality of life of at least one person. Preferably the invention will provide benefits to a large human population.

[0056] The invention may further comprise monitoring use by humans of the preferred substance, assessing safety, in a select population, expanding use to a larger population and monitoring members of said larger population for improved health or life conditions, especially improvement in a condition related to an associated disease.

[0057] Papain is marketed and used as a food supplement with dosing about 20-60 mg/day and suggested for treating swelling pain and inflammation at a dosage about 1500 mg/day. For example, twice daily or even about 3, 4, 5 or 6, even about 8, 9, 10 or more daily doses if taken as a candy or snack like popper, chew gum, or more, for example as a pill, etc., of about 5, 10, 20, 25, 30, 40, 50, 75, 100, 125, 150, 200, 250, 300, 500, 750, 1000 or more mg may be used.

[0058] Falcipains, malarial sourced cysteine proteases, have garnered interest medically as targets for fighting malaria. For example, a falcipain inhibitor is used to interfere with the malarial parasite's access to food. But, the enzymes can be put to use in an analogous manner to that of papain.

[0059] Cathepsin B has been used to induce apoptosis in several mammalian cells. It has also seen use as a dietary supplement to aid digestion. In ischemic injury cases inhibiting cathepsin B prevented significant loss of neurons in non-human primates and rodents. According to Wikipedia: in a transgenic mouse model for AD, inhibiting cathepsin B activity lessened memory deficit. But mice with higher levels of cathepsin B and human students performed better on memory tests. In these studies, cathepsin B was experimentally elevated. http://www.nprorg/sections/health-shots/2016/06/23/483245084/a-protein-thatmoves-from-muscle-to-brain-may-tie-exercise-to-memory

[0060] Monensin is used as an ionophoric antibiotic supplement for animal feed up to about 700 g per day. Since it has preference for monovalent ions, including H.sup.+, monensin alters pH and has noted effect on the golgi affecting terminal glycosylation and proteolytic cleavages. Monovalent ions whose cotransport (neutral exchange, e.g., Na.sup.+/H.sup.+ exchange, across plasma membranes) have been studied include sodium, potassium, lithium, rubidium, titanium and silver. Dosages can be selected as tolerated and deemed effective. Suggested dosages that will be expected to be patient dependent range from about 50 to 500 mg per day with typical dosage 50 to 200 mg twice daily. Monensin can be tolerated with food typically from 1 to 4 times per day as low as about 20 mg per meal up to about 100 mg multiple times per day. Monensin is popular for veterinary applications in meat and poultry production especially effective in controlling intracellular parasites. The therapeutic window is relatively narrow compared to most human drugs. Monensin also affects intracellular ion transport and related functions including intracellular protein transport and the H.sup.+ gradient responsible for ATP production. Beneficial effects from monensin with respect to anti-agglomeration may include inducing antioxidant protein system expression in the affected cells. Skin biopsies, plasma and/or other fluid or tissue assays, including, but not limited to: saliva, tears, urine renal, hepatic, pulmonary, muscle, etc. may be used to determine levels of effectiveness.

[0061] Glutathione is found in many tissues, being naturally produced primarily in the liver as an antioxidant. Glutathione has been used therapeutically to treat cataracts, glaucoma, asthma, memory loss, AD, Parkinson's etc.

http://www.webmd.com/vitamins-supplements/ingredientmono-717-GLUTATHIONE.aspx?activeIngredientId=717&activeIngredientName=GLUTATHIONE

[0062] A dose of 400-500 mg per day has been recommended as a supplement. Glutathione levels restored by a selenoprotein glutathione reductase.

[0063] The example continues by selecting one or a plurality of substances having characteristics similar to those of the above listed substances. Other proteases may be tested or other anti-oxidants may be included individually or as supplements in experimental protocols. The proteases may act as sinks, i.e., competitor molecules that distract the protease inhibitor from its usual target. Smaller molecules having the inhibitor binding domain, but not full enzymatic activity may be simpler to produce or administer and may have acceptable or even enhanced activity when compared to natural protease. Modified proteases that bind an inhibitor and then disrupt folding or cleave the inhibitor may be especially effective.

[0064] For this example, monensin, papain, a falcipain, and glutathione are the treatment cohorts with each given at three dosage levels. For preliminary studies 5 persons are at each dose for a total of 60 persons in the study.

[0065] Treatment may be guided in accordance with bioassays or testing protocols. Acceptance of a subject for treatment may be dependent on observations relating to symptoms and/or assays of one or more tissues or tissue samples. For example, genetic assays may be conducted to identify individuals at high risk for developing amyloidoses. For example, a mutation such as that related to L68Q cystatin C may be set as one simple threshold suggestive of treatment. Actual protein and/or plaque presence might also be set as a criterion for treatment. Treatment can be adjusted and repeated in accordance with a monitoring of disease progression or regression. Monitoring may precede and/or follow a treatment and may be repeated at random or defined intervals, for example, about seven days, about two weeks, about 30 days, about 45 days, about 60 days, about 90 days, about 120 days, about 180 days, about 360 days, and/or the like.

[0066] Monitoring can include imaging, functionality, bioassays, etc. Bioassay sources include but are not limited to: an integumentary biosample, a skin biosample, a buccal biosample, a mucus biosample, a blood biosample, a urinary biosample, a stool biosample, a muscle biosample, etc.

[0067] Such assaying may include at least one bioassay capable of determining amyloid deposit presence, cystatin C or fragment deposition, etc. and may involve a simple determination of the presence of the assayed substance or may involve quantitation and/or structure/size determination or the like.

[0068] Results of such monitoring events may be input into an algorithm, which may output a suggestion including one selected from but not limited to the group consisting of: at least one glutathione support compound, a dose relating to at least one glutathione support compound, a rate of delivering relating to at least one glutathione support compound and a route for said delivering relating to at least one glutathione support compound, etc.

[0069] Glutathione support compounds that might be used include but are not limited to: a sulfur containing compound selected from the group consisting of: sulfhydryls, thioethers, thioacetals, thioamino acids, thioproteins and thioesters. Such compound might be n-acetylcysteine, 2-mercaptoethanol, cysteine, glutathione, thioalkylate, furan-2-ylmethanethiol, grapefruit mercaptan, 2-propene-1-thiol, thioalkylates, thioredoxin, glutaredoxin, thiazolidinediones, methionine, etc.

[0070] Treatment may benefit from combination therapies. For example, an anti-inflammatory program may be advantageous for allowing continued activity of the glutathione supportive therapeutic(s). Macrophage and/or activity may interfere with access of the primary anti-plaque substances to the plaques and may in fact induce protein expression that increases expression of toxic amyloid. An anti-inflammatory compound may be one or more cytokine active substance, biosimilars and derivatives thereof and/or may be a synthetic compound, e.g., a small molecule, that inhibits inflammation. Small molecule anti-inflammatories including, but not limited to: sulinac, sulindac sulfide, pravadoline, naproxen, naproxen sodium salt, meclofenamate sodium, ibupropfen, S-ibuprofen, piroxicam, ketoprofen, S-ketoprofen, R-ibuprofen, Ebselen, ETYA, diclofenac, diclofenac diethylamine, flurbiprofen, fexofenadine, Pterostilbene, Pterocarpus marsupium, 9,12-octadecadiynoic acid, Ketorolac (tromethamine salt), NO-indomethacin, S-flurbiprofen, sedanolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac ibuprofen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)1H-indole-2,3-dione, aceclofenac, acetylsalicylic acid-d4, S-ibuprofen lysinate, loxoprofen, CAY10589, ZLJ-6, isoicam, dipyrone, YS121, MEG (mercaptoethylguanidine), etc. may be used in conjunction with the glutathione supportive compositions. Natural biomolecules such as interleukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11, IL-13, precursors, active fragments and/or derivatives, preferably derived from the recipient species may also be advantageously supplemented to assist in inflammation control. Specific cytokine receptors for IL-1, tumor necrosis factor-, and IL-18 may also function as proinflammatory cytokine inhibitors. Anti-inflammation actions of these compounds, in addition to modulating tissue damage from inflammatory responses, when used as a component in several embodiments of the present invention, in many cases will result in increased effectiveness of the treatment. I.e., slowing of additional plaque deposition, increased resorption of existing plaques, and decreased opportunity for plaque precursor compounds to react.

[0071] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

[0072] For an early test of effectiveness of glutathione supportive therapy in the treatment of HCCAA and similar disease involving plaque formation, human trials are planned using accepted and previously approved therapeutic interventions. Initial trials involve n-acetylcysteine based on its chemistry and historical acceptance in human therapies. Doses ranging from as low as 200 mg/day, but at least in the early trials, at higher levels to emphasize effect have been proposed with initial regulatory approvals in high risk HCCAA patients.

Applied Example

[0073] Three persons who had been identified through characteristic HCCAA symptoms confirmed by genetic screen to express L68Q cystatin C agreed to participate in a preliminary trial with a prototype drug to support antioxidant and other effects of GSH. N-acetylcysteine was used as a GSH-support/anti-cystatin-C-polymerization archetypical drug for conceptual proof and support of the hypotheses supporting this invention. All three patients showed disease arrest. One patient fully complied with the prescribed protocol. Two patients were only partially compliant. The fully compliant patient presented with a 50% reduction in plaques observed on biopsy.

[0074] In the partially compliant subject/patients, one showed a significant reduction of aggregated protein previously observed. The remaining non-compliant patient nevertheless showed disease arrest and may see improvement with future participation.

[0075] Treatments are continuing, augmented by confirmatory/advisory biopsies. Biopsy intervals may be approximately weekly, but longer intervals are envisioned as sufficient to monitor effects and dosages and to encourage compliance in testing and treatment maintenance. For example, biopsy intervals may be weekly, biweekly, monthly, bimonthly, quarterly, semi-annual, annual, etc. Biopsy appointments may be used both for treatment/disease monitoring, but also to maintain patient attention and interaction. Medical advisory panels and insurance issues may also be considered in determining the frequency and type(s) of biopsies.