CN1082819C - Abrogation of uiral resistance to nucleoside analogues by double-stranded RNAs - Google Patents
Abrogation of uiral resistance to nucleoside analogues by double-stranded RNAs Download PDFInfo
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Abstract
The rate of viral resistance developed during the course of treatment with antiviral nucleoside analogues is reduced by administering dsRNAs early in the treatment of the infection or in later stages when viral genetic mutation has occured to restore susceptibility of the virus to otherwise ineffective antiviral agents. Delaying and/or reducing the appearance of nucleoside analogue resistant retroviruses, particularly HIV, is achieved with mismatched dsRNAs notably in the peripheral blood mononuclear cells, especially the CD4 lymphocytes.
Description
Nucleoside analog is usually as antiviral agent, especially as anti-reversibility virus (retroviruses) agent.Virus experience genovariation or sudden change cause the relative drug resistance of these antiviral agent.In case the generation drug resistance, virus is bred rapidly, so quickened potential seizure of disease.The early deployment double-stranded RNA (dsRNA) that infects can reduce the speed that viral drug resistance occurs.Even infect the later stage, gene mutation takes place, and dsRNA also can recover the sensitivity of virus to other invalid antiviral agent.This point can be combined by two kinds of patterns of life-time service clinically and find out in the unpredictable consequence that treatment causes.This clinical effectiveness is, host immune function recovers greatly, and detectable virus is very little.This result uses any one antiviral agent unexistent separately.
The long-term treatment of viral disease, particularly reversible viral disease relevant (list of references 1 and 2) occur with viral Drug resistance.Ideal situation is that when using nucleoside analog to carry out chemotherapy, nucleoside can be inserted among the viral gene information, and causes genetic flaw or incomplete, thereby reduces the viral growth cycle efficieny.The ability that defective or incomplete viral offspring forms infection reduces.But, by modifying the gene structure of itself, drug resistance can appear in virus relatively, thereby even there is nucleoside analog, also can produce infective viral offspring.Typical gene variation appears at pol gene (i.e. the virus component that instructs anti-viral nucleoside to insert in the growth circulation first step), and making virus can be subjected to antiviral to block form influences.At present but best research example is the interaction between retroviral, for example HIV (HIV (human immunodeficiency virus)) and 3 '-azido-3 '-deoxythymidine, the latter also is referred to as AZT or zidovudine.Cause that AZT is had drug-fast mutation usually simultaneously to other medicines, for example didanosine (DDI) and zalcitabine (DDC) (being not limited to this two kinds of chemical compounds) drug resistance.
Had been found that before using the nucleoside analog treatment use the dsRNA of effective dose erroneous matching at reasonable time, the patient that can make HIV infect (the HIV positive) postpones or reduces, or not only postponed but also reduce the program that nucleoside analogue drug-resistant virus occurs.These programs make patient infect the later stage at HIV, when needing to use the nucleoside analog antiviral agent, to medicaments insensitive.
Also describe the dSRNA that uses the effective dose erroneous matching, but improved retrovirus infection patient's peripheral blood monokaryon hemocyte (PBMC) group, especially T
4Or CD
4Lymphocytic treatment procedure.
DsRNA contains the polyinosine of part uracil base or guanyl-and the complex of poly-cytidine, for example content from 1/4 to the 1/29 (poly I.poly (C of this class alkali base
4-29X＞U or G)).
The general formula of dsRNA can be rI
nR (C
11-14 'U)
nOr rI
nR (C
12' U)
nOther suitable example of dsRNA is discussed below.
The hydrogen bond (base stacking) that " the paired dsRNA of mistake " is used for describing between those marriage chains is complete relatively, and promptly hydrogen bond is interfered interrupted average in successive per 29 base pair residues during 1 base of less than." the paired dsRNA of mistake " should understand by this.
The present invention advocates the wrong paired dsRNA of use to be selected from poly (C
n' U) and poly (C
n' G) copolymerization nucleotide is the basis, and wherein n is 4 to 29 integer, and copolymerization nucleotide is by along poly-ribose cytidine key (rC
n) rI
nRI
nModify and insert not timing base (uracil or guanine) and the wrong paired analog of the complex of the poly-ribose inosinic acid that generates and poly-ribose cytidylic acid.In addition, by modifying poly-ribose inosinic acid (rI
n) the ribose skeleton, for example 2 '-O-methylribose residue is included in wherein, from poly (I) poly (C) the dsRNA wrong paired dsRNA that derives.The paired complex of mistake can use the high polymer of RNA-stabilisation, and for example polylysine or cellulose carry out compound.Carter and Ts ' o be at United States Patent (USP) 4,130, described rI in 641 and 4,024,222
nRC
N 'Mistake pairing analog in preferred analog, general formula is rI
n(C
11-14 'U)
nOr rI
nIr (C
29 'G)
N ', list of references is classified in these inventions as.According to the present invention, wherein the dsRNA of Miao Shuing generally is suitable for.Preferred wrong paired dsRNA is rI
n(C
11-14 'U)
nOr AMPLIGEN (HEN Resarch, Inc, Rocknille, MD USA), can buy lyophilized powder.
Other example of the wrong paired dsRNA that uses among the present invention comprises:
poly(I)·poly(C
4′，U)
poly(I)·poly(C
7′，U)
poly(I)·poly(C
13′，U)
poly(I)·poly(C
22，U)
Poly(I)·poly(C
20，U)
Poly (I) poly (C
29, U) and
poly(I)·poly Cp
23 G＞p
Be applicable to that implementing another kind of dsRNA of the present invention is the short chain dsRNA that determines structure, for example general formula is
5 '-block-(I)
n-blockade 3 '
3 '-block-(C)
n-block 5 ' oligonucleotide.Wherein all greater than 5 to less than 100, I is single phosphorylation inosine separately for m and n, and C is single phosphorylation cytidine, and the blockade base complementation on the blockade base on chain and the relative chain.Or general formula is
5 '-block-((I)
xA)
d-blockade 3 '
5 '-block-((C)
yU)
k-block 3 ' oligonucleotide.Wherein x and y be separately greater than 5 less than 25, and j and k equal 1 and less than 10 at least, and I and C are the same, and A is the nucleotide beyond the I, and U is base and the paired nucleotide of A.
In addition, the short chain oligonucleotide can have following structure:
5 ' (I)
n-hinge-(C)
m3 ' wherein n, m, the definition of I and C is the same.
These oligonucleotide can with relative chain on the not complementary chain of nucleotide on contain substituent group.These oligonucleotide are preferably stablized by the pairing of the inside of complementary non-homogeneous high polymer, and ideally, blockade base and hinge base or the two all contain the zone of complementary non-homogeneous high polymer.These oligonucleotide contain single last-of-chain ideally.These oligonucleotide are existing the description in PCT/US89/02172.
Patient needs root a tree name clinical improvements situation defeated 200 to the 700mg rIr (C of vein once in a week or once a day
11-14 'U).The consumption of dsRNA and administration number of times will make patient's systemic blood circulate in to be measured to the dsRNA level in the place away from transfusion part after the medication and reach 0.01 μ g to 1,000 μ g/ liter.
Illustrative nucleoside analog antiviral agent comprises Ziodovudine (resembling the AZT or zidovudine pyridine or the Retrovar that generally use here), promptly 3 '-nitrine-3 '-the deoxidation thynlidine, be to be used for because of HIV (human immunodeficiency virus) (HIV, HTLV-I, HTLV-II, HTLV-III, LAV, the similar information thing of ARV and various bacterial strains) the relevant complex situations with AIDS of AIDS that cause need the nucleoside analog antiviral agent of systemic treatment.Adult's dosage is administration 200mg per four hours of every day.The patient of a 70kg body weight, corresponding dosage is per four hours per kilogram of body weight 2.9mg.Every day per kilogram of body weight dosage with reaching 60mg.To show further that as the discussion of back during with the paired dsRNA coordination of mistake, the reversible viral dosage of the nucleoside analog of use is usually less than normal dose and custom consumption.
Fig. 1 is time (month number) table of describing 298 patient deaths or AIDS " systemic infection ", back AZT " late period " (circle) occurs with AZT " in early days " (grid) treatment before symptom occurs or symptom and treat and compare, adopt the patient's of no fatal HIV situation ratio to represent.
Fig. 2, but use dsRNA or it and AZT more in early days and use to the control of reversible viral growth with use retroviral ramp in the AZT case separately.In Fig. 2, HIV cultivates and is undertaken by list of references 3, and the PBMC of use is from example
#, to example
#3 cultivated 4 days, after 7 days and 14 days, collected PBMC, be dissolved among the GUSCN, and by the use molecular hybrid technical measurement HIVRNA that describes in the method.Mononuclear cell in the PBMC=peripheral blood; GUSCN is a cyanic acid guanidine solution, is used for dissolved cell and releasing virus material.
Fig. 3, when relatively dsRNA and AZT are as the single therapy agent during with placebo and dsRNA and AZT therapeutic alliance, CD in the long-term maintenance HIV disease on indicated all numbers
4Cell is pressed the relative effect of the middle qualitative changeization in the CD4T lymphocyte.
Fig. 4 is associated the natural law of AZT and dsRNA therapeutic alliance with the percent change of T4 level, show dsRNA Ampligen
T in the HIV disease
4Expand to the stable period that has exceeded independent use AZT expection the stable period of cell.Pointed out each member's of drug combination middle dosage.
Fig. 5 is Ampligen
Natural law and T with the AZT coupling
4The average percentage of cell changes (increase) and is associated, and shows Ampligen
T in increase and/or the stable HIV disease
4Cellular level still exceeds this time cycle at AZT in the effective time cycle.
Fig. 6 be 12 the middle of the month placebo, use AZT, Ampligen separately
Single therapy and Ampligen
There is not fatal patient's HIV ratio diagram during with the AZT therapeutic alliance.
In Fig. 4 and Fig. 6, indicate near the bracket of patient's number relevant data point, in Fig. 3 and Fig. 5, indicate with N=.
In Fig. 2, according to the method for describing in the list of references 3, use is finished HIV from the peripheral blood mononuclear cell of example 1 and 3 and is cultivated altogether.Cultivated altogether 4 days, and after 7 days and 14 days, collected the peripheral blood mononuclear cell and also be dissolved in the cyanic acid guanidine solution, the latter is used for dissolved cell and releasing virus material.Measure HIV RNA with molecular hybrid, will describe in detail below.
Fig. 1 explanation is (for example weightless at " in early days " of the Veterans of the abundant announcement of hiv infected patient group, before symptoms such as night sweat occur) or " late period " (after comprising that promptly this class symptom by the relevant infection of fungus or bacterial HIV occurs) when using the AZT treatment, the development of fatal situation (developing into the AIDS or the death of systemic infection).
Can find out obviously that from Fig. 1 " in early days " uses not life-saving of AZT.The blood sample of taking from the patient of having developed fatal situation shows the AZT drug-resistant virus, and (this paper is with AZT
Expression) concentration increases, and the patient who did not still have fatal situation in about 40 months observation cycles generally has couple AZT to become responsive virus (AZTS).
Below, feature is more fully: although treat from AZT, the relative AZT sensitivity of the isolating on one's body typical HIV chorista of the patient that disease still develops, and these results are compared with comprising the viral chorista that obtains the hepatitis virus that the patient of relative good control is separated on one's body from disease.Clearly, AZT appears
Virus can shorten the vital stage.But typical human body retroviral HTLV-1, HTLV-2, HTLV-3 and the virus of breeding by same mechanism comprise some hepatitis viruss.
The invention that improves this present an open question is described this inventor.This invention can be implemented by number of ways, and these approach comprise: (a) before virus is exposed to AZT or other analog, use the dsRNA of specific type, reduce AZT
Appearance (b) by the anti-dsRNA that adds in system, overcome AZT
The deadly character of HIV (or other viral drug resistance analog).DsRNA/ nucleoside system has shown antagonism AZT
The unexpected synergism of HIV and not have corresponding collaborative toxicity, this like this system be unique unexpected useful combination medicine really, use correctly can be saved life.
The inventor's study tour how to unite and use Ampligen
AZT reduces the problem that HIV-virus is caused, in the research virus acellular from or accept Ampliger
Treat separately or accept AZT and treat or accept Ampligen separately
The patient of-AZT therapeutic alliance, this virus is used to infect fresh human peripheral liquid cell, and this blood blood born of the same parents are exposed on Ampligen in advance
, AZT or Ampligen
Among AZT.Come from only accept the patient of AZT single therapy more than 1 year virus to insensitive (the 0.5uMAZT=4% suppression ratio of AZT; ED
50＜5uM), but as original HIV virus to single Ampligen sensitivity (5ug/ml, Ampligen
-AZT coupling is than list-Ampligen
Can produce bigger HIV suppression ratio (93%).Come from and accept single Ampligen
Treatment or Ampligen
The patient's of-AZT therapeutic alliance virus has shown the relative drug resistance to AZT, to the Ampligen sensitivity
, and to Ampligen
-AZT drug combination even bigger sensitivity is arranged.According to patient's different treatment plans, relatively use the result of many different virus chorista gained, can obviously see, before being exposed to AZT, just accepted Ampligen
Treatment patient's virus is greater than the virus that comes from the patient who has at first accepted AZT for the sensitivity of AZT (and other nucleoside analog).
The Drug resistance of table 1 HIV chorista
| HIV separates | Ampligen ED 50 (μg/ml) | AZT ED 50 (μg/molar) | Association index a | The AZT Phenotype |
| H112-2 6910-6 | 2 3 1 1 .5 1 .5 2 | .03 2 0.6 0.2 ＞5 ＞5 ＞5 ＞5 | 0.5 0.2 0.4 0.2 0.2 0.8 0.2 0.3 | Responsive resistance part resistance " resistance " " " |
A=AZT-Ampligen
Interact by waiting number assay determination (list of references 4).Association index (CI) is defined as CI+ (Ac/As)+(Be/Bs), and wherein Ac and Bc are the drug level that uses in the therapeutic alliance, and As and Bs are the drug level that produces the therapeutic alliance same effect when using separately.When CI＜1, medicine is worked in coordination with; When CI=1, medicine add and; When CI＞1, the mutual antagonism of medicine.ED
50For suppressing the external dosage of 50% virus breeding.
The inventor shows typical embodiment of the present invention in Fig. 2, uses Ampligen in embodiments in early days
Or use simultaneously with AZT, in fact can produce substantial benefit, but resemble the bulk concentration of the so harmful virus of retroviral such as reduction.The generation curve of the rapid rising of the viral RNA of representing with open loop (ribonucleic acid) is controlled the indication of viral growth, and two horizontal lines are represented to produce by therapeutic alliance virus and are well controlled.Open loop explanation AZT among Fig. 2
Virus develops rapidly, so just becomes the classical symptom of patient among Fig. 1, and these patients are when giving AZT separately, toward the development in more late period of disease.
Drug resistance Phenotype (table 1) whatsoever, some dsRNA, especially wrong paired dsRNA if with AZT (or other nucleoside analog) coupling, but then show coordinate repression to retroviral.H112-2 and 6910-6 are the HIV phenotype clones who shows typical sensitivity and drug-fast very characterization respectively.And example
#1 to example
#The 6th, (for example routine from being exposed to various systems
#1,2,3 patients are identical with patient among Fig. 2, and for example 4,5,6 patients resemble and advise among Fig. 1, at first treat separately with AZT) especial patient in isolated virus.
When drug combination clinically, the result is unexpected once more, and not measurable according to the clinical observation of two kinds of medicines of independent use (single therapy).For example, use AZT (with other analog) to make some immunocytes increase (list of references 5) in short-term separately, these immunocytes are called cd4 cell, but they the easiest be some retrovirals and some hepatitis viruss (particularly HHV6) attack.After increasing in short-term (seeing about 12 to 16 weeks), because HIV propagation and AZT occurs
HIV, immunocyte worsens (Fig. 3).Number in the bracket is called the main body number of research.Outside comparing, independent cooperation Ampligen
All the time cause CD
4Cell number is in horizontal line (Fig. 3, for example immuning cell number neither increases also and do not reduce, in other words, cell number stabilisation), Ampligen
Dosage about 400 to 500mg, weekly twice, intravenously administrable.
Patient accepts AZT and treats separately, oral 200mg per four hours of every day (1200mg/ day).Ampligen
The independent patient of treatment group twice of the minimum dosage of vein (mean dose scope for 463-555mg) weekly weekly.(patient who accepts therapeutic alliance who shows among Fig. 4 also fails with 400mg typical A mpligen for twice weekly
Dosage, and the AZT of average companion's usefulness dosage range every day 300 to 540mg).
Placebo conforms to the evidence that disease process unfeelingly fails with the trend that AZT single therapy group (after 16 weeks) T4 lymphocyte intermediate value changes.Effectively treatment is not intervened, and placebo patient's lymphocytic intermediate value change count descends.After at first increasing, though accept the patient of AZT single therapy also experience they T 4 cell intermediate values counting decline and AZT appears
HIV.This decline parallels since the decline that occurred in the 12nd week occurring among the patient with placebo treatment.
Treat separately and placebo group 12 week beginning T according to AZT
4The linear regression line statistical method that the cell intermediate value change to constitute is slope relatively, shows they and intermediate value T
4Unconverted 0 slope of cellular level has statistics difference (p＜0.01 and p＜0.01 is arranged respectively)." no change " typically represents the stable of amynologic disease, " negative slope " expression disease progression, and optimal consequence to be positive section lead, expression disease (immunity) is recovered, but this can not reach by the single therapy system of research.
The AZT single therapy of placebo is after 12 weeks, Ampligen
Eliminated the CD that expects separately
4Descend.Ampligen
Continuous intermediate value CD in the treatment
4The slope of regression line of level and the no CD of reflection
4The horizontal line of loss cell does not all have significant difference in the whole time.
Slope is compared with horizontal line (no change)
The p value
Ampligen
Not statistically significant p＞0.2
AZT significant difference p＜0.01
Placebo significant difference p＜0.01
Though Ampligen
Single therapy (Fig. 3) can eliminate the serious decline of the intermediate value T4 lymphocyte of in two groups of patients of placebo and AZT treatment, all seeing (after 12 weeks in short-term raise), but average T 4 levels do not raise.And at Ampligen
In the group, observed little (no difference of science of statistics) intermediate value T4 lymphopenia (Fig. 3) can be produced more persistent T4 stabilisation and reverse easily more than twice 200mg by dosage being increased to weekly in 1 year.At Ampligen
In the single therapy group since 12 weeks observed intermediate value T4 cells variation formation the regression line slope and show stable disease 0 between do not have significant difference.The Ampligen that Fig. 3 provides
Single therapy group, AZT single therapy group or placebo treatment group have about equally intermediate value and average absolute T4 (also claiming CD4) lymphocyte level.Then I they with accept Ampligen
Compare with new group of AZT therapeutic alliance.This new group abswolute level that in fact has the prognosis indication of lower (about 33%) intermediate value and this HIV infection that increases the weight of, thus show that they have bigger death risk or other " fatal event ".
Following table has provided Ampligen
With every mm in the AZT long term maintenance HIV disease
3The relative effect of cd4 cell.
Table 2
| Treatment | Patient's number | Baseline | The absolute CD of intermediate value in 1 year 4Cellular change | |
| Intermediate value | Meansigma methods | |||
| Ampligen+AZT Ampligen List is singly used placebo with AZT | 11 54 260 255 | 201 311 350 * 350 * | 248 350 355 356 | +15 -15 -28 * -59 * |
As what in Fig. 3, see, finish 59 cells of the absolute T4 lymphocyte count minimizing of patient's intermediate value (4.9 cells of minimizing in about every month) that placebo is used in treatment in a year; The patient who accepts the AZT single therapy reduces 28 cells (2.3 cells of minimizing in about every month); Accept Ampligen
The patient of single therapy only reduces 15 cells (average every month reduce approximately 1.25 cells).But, accept Ampli-gen
With AZT therapeutic alliance group, this group has minimum pretreat intermediate value and average absolute T4 lymphocyte level (so being among the maximum risk), in fact having experienced the absolute T4 cellular level of intermediate value has increased by 13 cells, even after the therapeutic alliance 1 year, still like this.These results are summarised in the table 2, and are listed as more in detail among Fig. 4.
Fig. 4 has illustrated intermediate value T in a year of therapeutic alliance
4The continuous variation of lymphocyte level, this therapeutic alliance should with the Ampligen among Fig. 3
Single therapy, AZT single therapy and placebo effect are compared.The baseline root a tree name that is used for comparison begins the continuously absolute T of the patient who measured immediately in three months before the therapeutic alliance
4The meansigma methods of lymphocyte count is calculated.
In 90 day cycle among Fig. 3 of observed increase and original report the preliminary effect of observed AZT single therapy conform to.But, that is seen continued to increase the demonstration significant difference from 180 days to 540 days the therapeutic alliance, and this does not observe in the patient who accepts the AZT single therapy.(the nonparametric analysis has confirmed T in a year
4Counting increases, and has statistical significance (p＞0.05).Why carrying out this analysis, is because relatively little sample number makes that possible T horizontal distribution is undesired).So, T
4It is longer than 3 to 6 months increase in short-term of AZT one single treatment expectation that lymphocyte increases the time that continues, and this result must come from the existence of dsRNA.In addition, when using the AZT of relative low dosage and dsRNA, also see this effect.This observation and being consistent of previously under the situation that is low to moderate 200mg dosage, seeing.Intravenous injection twice weekly, continues 1 to 4 months, Ampligen
Single therapy can stablize untreated hiv infected patient (T4=60-300 cell/mm
3) the T4 cell of expectation reduce, if patient continued this treatment 5 to 8 months, can keep this effect (Fig. 3).
Average percentage according to T4 lymphocyte count in dsRNA and AZT therapeutic alliance 135 days to 630 days changes, and the regression line that obtains sees Fig. 5.The average of each patient's continuous T lymphocyte count in 91 to 180 days of therapeutic alliance is as the baseline of determining that percentage changes.This baseline is selected as separation, and in the back of this point, the AZT of estimation is to T
4The influence of level generally disappears.
Use statistical method, the slope of the positive slope of the regression line and 95% credible limit is pointed out Ampligen
Successfully stoped the untreated patient (4-6 cell/moon) that expects and long-term AZT single therapy patient's (more than 6 cell/moons) long-term T with the AZT therapeutic alliance
4Cell reduces.So, T has in fact been kept in therapeutic alliance indefinitely
4Level, and the persistent period is observed more much longer than original AZT single therapy, and this point has just in time illustrated the present invention at the nucleic acid drug-resistant virus, the basic purposes in the particularly reversible viral therapy.
At last, Fig. 6 accepts placebo, AZT single therapy, Ampligen by statement as patient
Single therapy, perhaps Ampligen
During with the AZT therapeutic alliance, develop into the ratio of AIDA infection/lymphoma (" fatal event "), confirmed effectiveness of the present invention.
Point out that as Fig. 6 accepting has about 10% experience fatal event in 12 months observation cycle among the patient of placebo.Patient's number of beginning, 6th month and 12nd month of research indicated in bracket.In this period, accept to have among the patient of AZT about 4% experience fatal event.Should be pointed out that the tumor (list of references 6) that independent use AZT can expect formation especially, be avoided by therapeutic alliance.Use Ampligen
During with the AZT therapeutic alliance, at absolute T
4Lymphocyte count is greater than 115 cell/mm
3Patient in, the unmanned fatal event that takes place, even those are because the intermediate value CD on the baseline before the therapeutic alliance
4Level has only 201, and immune system obviously worsens, and is the patient who is in the very big danger like this, also is like this.
With to put into practice the present invention consistent, after the basis of control virus replication is accomplished fluently, can add lymphokine advisably such as interleukin and interferon one class.
List of references 1. Larder, B.A.et al pp.436-441 Antimicrobial
Agents and Chemotherapy.Vol.34，March 1990.2. Larder，B.A.et al.pp.1731-1734，Science，
Vol.243，1989.3. Jackson，J.B.et al.pp.1416-1418.Journal
Clin.Microbiology，Vol.216，1990；Thompson，
J.D.et al.pp.371-378，Analytical Biochem.
Vol.182，1989.4. Berenbaum，M.C.pp.269-333.Advances in Cancer
Research Vol.35，1981.5. Fischl，M.et al.p.727-733，Annals of
Internal Medicine Vol.112，1990.6. Pluda，J.M.et al pp.276-282
Annals of Internal Medicine，Vol.113(number
4，1990
Claims (18)
1.dsRNA be used for improving the purposes of the medicine that has infected the monocytic sickness rate of the HIV of anti-nucleoside analog virosis human peripheral liquid in preparation.
2. the purposes of claim 1, wherein said cell is the CD4 lymphocyte.
3. the purposes of claim 1, wherein said dsRNA is and the compound polyadenylic acid of polyuridylic acid.
4. the purposes of claim 3, wherein said dsRNA is the complex of polyinosine and poly-cytidine, wherein contains 1/4 to 1/29 uracil or guanine base.
5. the purposes of claim 4, wherein said dsRNA is rI
nR (C
11-14 'U)
n, perhaps said dsRNA contains the bond fission zone and shows rI
nR (C
11-14 'U)
nFavourable treatment rate character.
6. the purposes of claim 3, wherein the content of dsRNA should make that this dsRNA level reaches 2 to 1000 μ g/ml in the circulation of patient's systemic blood in the compositions.
7. the purposes of claim 1, wherein said dsRNA is the oligonucleotide of short chain, the general formula that defines this oligonucleotide is:
5 '-block-(I)
n-block 3 '
3 '-block-(C)
m-wherein m and n are separately greater than 5 and less than 100 to block 5 ', and I is single phosphorylation inosine, and C is single phosphorylation cytidine, or
5 '-block-[(I)
xA]
j-block 3 '
3 '-block-[(C)
yU]
k-block 3 '
Wherein x and y be separately greater than 5 and less than 25, and j and k are at least 1 and less than 10 separately, and the definition of I and C is the same, and A is for being not the nucleotide of I, and U is base and the paired nucleotide of A, or
5 ' (I)
n-hinge-(C)
m3 ' n wherein, m, the definition of I and C is the same, condition be a blockade base on the chain with relative chain on the complementation of blockade base.
8. the purposes of claim 7, wherein oligonucleotide stablize by the pairing of the inside of complementary non-homogeneous high polymer, and blockade base or hinge base or the two all contain the zone of complementary non-homogeneous high polymer.
9. the purposes of claim 1, wherein said dsRNA is rI
nR (C
11-14 'U)
n
10.dsRNA be used for delaying, reducing or promptly delay and reduce the purposes of the medicine of anti-nucleoside analog virus appearance in preparation with HIV viral infection personnel.
11. the purposes of claim 10, wherein said cell is the CD4 lymphocyte.
12. the purposes of claim 10, wherein said dsRNA is and the compound polyadenylic acid of polyuridylic acid.
13. the purposes of claim 12, wherein said dsRNA is the complex of polyinosine and poly-cytidine, wherein contains 1/4 to 1/29 uracil or guanine base.
14. the purposes of claim 13, wherein said dsRNA is rI
nR (C
11-14 'U)
n, perhaps this dsRNA contains the bond fission zone and shows rI
nR (C
11-14 'U)
nFavourable treatment rate character.
15. the purposes of claim 12, wherein the content of dsRNA should make that this dsRNA level reaches 2 to 1000 μ g/ml in the patient's systemic blood circulation in the compositions.
16. the purposes of claim 10, wherein dsRNA is the oligonucleotide of short chain, and the general formula that defines this oligonucleotide is:
5 '-block-(I)
n-block 3 '
3 '-block-(C)
m-wherein m and n are separately greater than 5 and less than 100 to block 5 ', and I is single phosphorylation inosine, and C is single phosphorylation cytidine, or
5 '-block-[(I)
xA]
j-block 3 '
3 '-block-[(C)
yU]
k-block 3 '
Wherein x and y be separately greater than 5 and less than 25, and j and k are at least 1 and less than 10 separately, and the definition of I and C is the same, and A is for being not the nucleotide of I, and U is base and the paired nucleotide of A, or
5 ' (I)
n-hinge-(C)
m3 ' n wherein, m, the definition of I and C is the same, condition be a blockade base on the chain with relative chain on the complementation of blockade base.
17. the purposes of claim 16, wherein oligonucleotide stablize by the inside of complementary non-homogeneous high polymer pairing, and blockade base or hinge base or the two all contain the zone of complementary non-homogeneous high polymer.
18. the purposes of claim 10, wherein said dsRNA is rI
nR (C
11-14 'U)
n
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68620091A | 1991-04-16 | 1991-04-16 | |
| US07/686,200 | 1991-04-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1068035A CN1068035A (en) | 1993-01-20 |
| CN1082819C true CN1082819C (en) | 2002-04-17 |
Family
ID=24755338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92102227A Expired - Fee Related CN1082819C (en) | 1991-04-16 | 1992-04-06 | Abrogation of uiral resistance to nucleoside analogues by double-stranded RNAs |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0581906A4 (en) |
| JP (1) | JPH06507624A (en) |
| CN (1) | CN1082819C (en) |
| AU (1) | AU671800B2 (en) |
| CA (1) | CA2102221A1 (en) |
| IE (1) | IE920873A1 (en) |
| MX (1) | MX9201711A (en) |
| PT (1) | PT100340A (en) |
| WO (1) | WO1992018004A1 (en) |
| ZA (1) | ZA922755B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4820696A (en) * | 1985-08-26 | 1989-04-11 | Hem Research, Inc. | Modulation of aids virus-related events by double-stranded RNAS |
| US4795744A (en) * | 1986-07-17 | 1989-01-03 | Hem Research, Inc. | Modulation of AIDS virus-related events by double-stranded RNAS |
| US4945082A (en) * | 1985-08-26 | 1990-07-31 | Hem Research, Inc. | Controlled dsRNA therapy for human viral infections |
| US4950652A (en) * | 1987-03-23 | 1990-08-21 | Hem Research, Inc. | dsRNAs for combination therapy in the treatment of viral diseases |
-
1992
- 1992-03-12 CA CA002102221A patent/CA2102221A1/en not_active Abandoned
- 1992-03-12 EP EP92917298A patent/EP0581906A4/en not_active Withdrawn
- 1992-03-12 WO PCT/US1992/001972 patent/WO1992018004A1/en not_active Application Discontinuation
- 1992-03-12 AU AU18718/92A patent/AU671800B2/en not_active Ceased
- 1992-03-12 JP JP4510192A patent/JPH06507624A/en active Pending
- 1992-03-19 IE IE087392A patent/IE920873A1/en unknown
- 1992-03-20 ZA ZA922755A patent/ZA922755B/en unknown
- 1992-04-03 PT PT100340A patent/PT100340A/en not_active Application Discontinuation
- 1992-04-06 CN CN92102227A patent/CN1082819C/en not_active Expired - Fee Related
- 1992-04-13 MX MX9201711A patent/MX9201711A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0581906A4 (en) | 1997-07-23 |
| CA2102221A1 (en) | 1992-10-17 |
| AU671800B2 (en) | 1996-09-12 |
| EP0581906A1 (en) | 1994-02-09 |
| WO1992018004A1 (en) | 1992-10-29 |
| AU1871892A (en) | 1992-11-17 |
| IE920873A1 (en) | 1992-10-21 |
| ZA922755B (en) | 1993-04-28 |
| MX9201711A (en) | 1992-10-01 |
| JPH06507624A (en) | 1994-09-01 |
| PT100340A (en) | 1993-07-30 |
| CN1068035A (en) | 1993-01-20 |
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