US20210145960A1 - Prophylactic protection against viral infections, particularly hiv - Google Patents
Prophylactic protection against viral infections, particularly hiv Download PDFInfo
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- US20210145960A1 US20210145960A1 US17/064,215 US202017064215A US2021145960A1 US 20210145960 A1 US20210145960 A1 US 20210145960A1 US 202017064215 A US202017064215 A US 202017064215A US 2021145960 A1 US2021145960 A1 US 2021145960A1
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- ranpirnase
- enzymatically
- vehicle
- infection
- ribonuclease
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Definitions
- the disclosure relates to prophylactic protection against viral infections, and more particularly relates to antiviral prophylactic protection that requires neither injection nor oral administration of a prophylactic agent.
- the invention relates to use of an enzymatically-active ribonuclease, and particularly use of ranpirnase, to prophylactically protect an individual from viral infections such as human immunodeficiency virus (“HIV”).
- HIV human immunodeficiency virus
- ranpirnase is active against HIV.
- an experiment has shown something unexpected, namely, that topically-applied ranpirnase acts as a microbicide, i.e. that ranpirnase can prevent cells from becoming infected with HIV.
- rectal tissue biopsies taken from HIV-uninfected individuals were incubated in solutions containing a mixture of ranpirnase and HIV. The explanted tissues were then cultured and supernatant was collected at intervals. The supernatant was assayed to quantify the amount of p24 antigen and to thereby determine the severity with which the tissues were infected with HIV.
- ranpirnase had a prophylactic effect on the explanted tissues; exposing the tissues to ranpirnase diminished the susceptibility of the tissues to HIV infection in a dose-dependent manner.
- a topical pharmaceutical composition consisting essentially of a therapeutically effective amount of an enzymatically-active ribonuclease and a viscous vehicle that does not unacceptably interfere with the enzymatic activity, wherein the vehicle is selected from the group consisting of a gel, a serum, or a lotion.
- the ribonuclease is ranpirnase and the vehicle is K-Y® Brand Jelly.
- This topical pharmaceutical composition is particularly well-suited for prophylactic application of ranpirnase (or another enzymatically-active ribonuclease) because the vehicle does not unacceptably interfere with the enzymatic activity of the ribonuclease and the viscosity of the vehicle allows the composition to remain where it has been applied so that the active pharmaceutical ingredient (e.g. ranpirnase)—does not run off.
- the active pharmaceutical ingredient e.g. ranpirnase
- ranpirnase topical application of ranpirnase is not the only way to administer it for prophylactic protection. It is also believed possible to protect an individual against a virus by infecting the individual with human microbiota into which ranpirnase DNA has been transfected, or by dispensing the ranpirnase using an intravaginal ring.
- FIG. 1 graphs the cumulative HIV infection of 15 individual rectal tissue biopsies in the herein-described experiment as a function of ranpirnase concentration
- FIG. 2 graphs the cumulative averaged HIV infection of 5 rectal tissue biopsy triplets in the herein-described experiment as a function of ranpirnase concentration
- FIG. 3 graphs the data graphed in FIG. 2 in a different format to clearly show the standard error of the mean at each ranpirnase concentration
- FIG. 4 shows a vaginal ring such as would be used in a third embodiment of the invention.
- Ranpirnase is a proteinaceous enzymatically-active ribonuclease having the amino acid sequence of SEQ ID NO:1, previously disclosed and claimed in U.S. Pat. No. 5,559,212.
- the fifteen tissue explants were arranged into five groups of three, with each group of three being incubated for two hours in a single one of these mixtures (one group is incubated in the control). The tissue explants were then washed multiple times and cultured at 37° C. and 5% CO 2 for fourteen days, during which interval supernatant was collected on Days 3, 7, 10, and 14.
- the culture medium was made up of equal parts of complete RMPI and Zosyn® 50 mg/mL, with 500 mL of complete RMPI being made up of
- the severity of HIV infection of the tissue explants was determined by assaying the supernatant for HIV-1 p24 antigen using the AlphaLISA platform.
- the efficacy endpoint was the tissue explant weight adjusted Day 14 cumulative HIV-1 p24.
- increasing concentration of ranpirnase caused a dose-dependent reduction in HIV-1 p24 antigen in the tissue explants.
- the statistical significance p of the displayed data is shown in the Figures; whether the data are averaged or not, the results for 0.00 ⁇ g/mL, 0.06 ⁇ g/mL, and 0.6 ⁇ g/mL concentrations of ranpirnase are below the 5% level of significance.
- results for 6.00 ⁇ g/mL and 66 ⁇ g/mL concentrations of ranpirnase are below the 1% level of significance where the results of each group of three tissue explants are averaged, and below the 0.1% level of significance where the results of each tissue explant is taken individually.
- the standard error of the mean is also shown by the vertical lines shown by themselves in FIG. 3 and superposed on the bars in FIGS. 1 and 2 .
- the standard error of the mean is smaller than in instances wherein the level of significance is less stringent (less than 5%).
- the topical pharmaceutical composition disclosed in the above-referenced parent patent application is used as a microbicide, and is topically applied to an individual who is to be protected. Further advantageously, the topical pharmaceutical composition can be applied to body regions that might be exposed to HIV during sexual intercourse
- the enzymatically-active ribonuclease can be ranpirnase.
- the “805 variant” (SEQ ID NO:2)is over 90% homologous to ranpirnase, in that the amino acid sequences of the two ribonucleases differ at only three positions (positions 11, 20, and 103) and has similar antiviral activities. Furthermore, it is known that the active site of ranpirnase is located at its N-terminal, and since the N-terminal amino acid sequences of ranpirnase and the '805 variant are identical, it follows that they will encode identical active sites. Thus, a person of ordinary skill in this art would expect the '805 variant to have the same prophylactic effect as ranpirnase has.
- mucosal tissues e.g. the vagina, the rectum
- E. coli and Lactobacillus are part of the microbiota in those regions.
- Ranpirnase DNA can be transfected into E. coli or Lactobacillus (or both) and the thus-modified E. coli or Lactobacillus introduced into the subject.
- the modified E. coli or Lactobacillus would then infect the subject and thereby produce ranpirnase in the mucosal tissues involved.
- other bacteria could be used to prophylactically protect other tissues against other viral infections.
- probiotic E. coli into which ranpirnase DNA had been transfected could be used to protect against viral infections of the digestive tract.
- saprophytic Streptococcus could be delivered to protect a subject's external genitalia against HIV.
- a third preferred embodiment of the invention is suitable for use by women.
- an intravaginal ring 10 ( FIG. 4 ) of a suitably porous and biocompatible material (such as is described below) is impregnated with ranpirnase and inserted into the vagina, where the ranpirnase is dispensed.
- the ranpirnase may be mixed with other agents (e.g. dispersing agents).
- Intravaginal rings are known and are used to dispense birth control drugs as well as dapivirine (a candidate microbicide now in clinical trials).
- An exemplary composition of such a ring is disclosed at Table 2 of Holt, et al., Antimicrobial Agents and Chemotherapy , Vol. 59, No. 7, pp. 3761-3770 (July, 2015), the disclosure of which is incorporated herein by reference.
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
An experiment has shown that ranpirnase is a microbicide. It is believed that topical application of a topical pharmaceutical composition consisting essentially of a prophylactically effective concentration of an enzymatically-active ribonuclease (e.g. ranpirnase) and a viscous vehicle that does not unacceptably interfere with the enzymatic activity (e.g. K-Y® Brand Jelly) will prophylactically protect an individual from a sexually-transmitted viral infection, particularly HIV. It is also believed that e.g. ranpirnase can be delivered to tissues of an individual who is to be prophylactically protected against viral infections by transfecting ranpirnase DNA into human microbiota and exposing the individual to the thus-modified human microbiota. It is also believed that ranpirnase can be delivered to a woman who is to be prophylactically protected against a sexually-transmitted viral infection by use of an intravaginal ring that has been impregnated with ranpirnase.
Description
- This is a continuation application of U.S. patent application Ser. No. 15/582,133 filed Apr. 28, 2017, which claims priority to U.S. Provisional application No. 62/367,050 filed Jul. 26, 2016. This application is also a continuation-in-part of application Ser. No. 14/793,920, filed Jul. 8, 2015, which is a continuation-in-part of application Ser. No. 14/462,520, filed Aug. 18, 2014. The entire disclosure of these applications are hereby expressly incorporated herein by reference for all purposes.
- The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: TAMI_014_02US_SeqList_ST25.txt, date recorded: Apr. 28, 2017, file size 4 kilobytes).
- The disclosure relates to prophylactic protection against viral infections, and more particularly relates to antiviral prophylactic protection that requires neither injection nor oral administration of a prophylactic agent. In its most immediate sense, the invention relates to use of an enzymatically-active ribonuclease, and particularly use of ranpirnase, to prophylactically protect an individual from viral infections such as human immunodeficiency virus (“HIV”).
- Sexually transmitted infections, and particularly HIV, pose a significant public health threat. At present, individuals wishing to protect themselves against such infections must rely upon mechanical measures (such as condoms and dental dams) that prevent them from coming into contact with their partner's bodily fluids, which may contain HIV. These measures are non-optimal because some individuals are reluctant to use them. More recently, the use of orally administered antiretrovirals (e.g. tenofovir) has been postulated as pre-exposure prophylactic treatment. While oral prophylaxis is effective, it suffers from significant disadvantages. Oral prophylaxis must be used consistently for a prolonged period and its effectiveness is reduced or even eliminated if the patient is not fully compliant. Other oral medications can adversely affect the efficacy of oral prophylaxis. And, the effectiveness of an orally administered drug can be seriously compromised if a patient suffers from nausea or from diarrhea.
- It would be advantageous to provide prophylaxis against sexually transmitted infections, and more particularly against HIV, that did not require the use of mechanical measures such as condoms and dental dams and that did not need to be administered orally or by injection.
- It is known that ranpirnase is active against HIV. However, an experiment has shown something unexpected, namely, that topically-applied ranpirnase acts as a microbicide, i.e. that ranpirnase can prevent cells from becoming infected with HIV. In this experiment, rectal tissue biopsies taken from HIV-uninfected individuals were incubated in solutions containing a mixture of ranpirnase and HIV. The explanted tissues were then cultured and supernatant was collected at intervals. The supernatant was assayed to quantify the amount of p24 antigen and to thereby determine the severity with which the tissues were infected with HIV.
- The assays showed that severity of HIV infection in the tissues was affected by the concentration of ranpirnase in the solution. As ranpirnase concentration increased, the level of HIV in the supernatant decreased. Hence, this experiment demonstrated that ranpirnase had a prophylactic effect on the explanted tissues; exposing the tissues to ranpirnase diminished the susceptibility of the tissues to HIV infection in a dose-dependent manner.
- This experiment is strong evidence that an individual can be prophylactically protected from viral sexually transmitted diseases such as HIV by applying ranpirnase topically to body regions (e.g. genitalia, rectum, mouth) that might be exposed to HIV during sexual intercourse, prior to (or even during) sexual intercourse.
- The above-referenced parent patent application discloses a topical pharmaceutical composition consisting essentially of a therapeutically effective amount of an enzymatically-active ribonuclease and a viscous vehicle that does not unacceptably interfere with the enzymatic activity, wherein the vehicle is selected from the group consisting of a gel, a serum, or a lotion. Advantageously, the ribonuclease is ranpirnase and the vehicle is K-Y® Brand Jelly.
- This topical pharmaceutical composition is particularly well-suited for prophylactic application of ranpirnase (or another enzymatically-active ribonuclease) because the vehicle does not unacceptably interfere with the enzymatic activity of the ribonuclease and the viscosity of the vehicle allows the composition to remain where it has been applied so that the active pharmaceutical ingredient (e.g. ranpirnase)—does not run off.
- However, it is believed that topical application of ranpirnase is not the only way to administer it for prophylactic protection. It is also believed possible to protect an individual against a virus by infecting the individual with human microbiota into which ranpirnase DNA has been transfected, or by dispensing the ranpirnase using an intravaginal ring.
- Although this experiment was only carried out using ranpirnase, there is at least one other ribonuclease (identified below) that is highly homologous to ranpirnase and that has similar antiviral activities. For reasons set forth below, it is believed that any such ribonuclease will be a microbicide and will have similar prophylactic effects.
- The invention will be better understood with reference to the exemplary and non-limiting drawings, in which:
-
FIG. 1 graphs the cumulative HIV infection of 15 individual rectal tissue biopsies in the herein-described experiment as a function of ranpirnase concentration; -
FIG. 2 graphs the cumulative averaged HIV infection of 5 rectal tissue biopsy triplets in the herein-described experiment as a function of ranpirnase concentration; -
FIG. 3 graphs the data graphed inFIG. 2 in a different format to clearly show the standard error of the mean at each ranpirnase concentration; and -
FIG. 4 shows a vaginal ring such as would be used in a third embodiment of the invention. - Ranpirnase is a proteinaceous enzymatically-active ribonuclease having the amino acid sequence of SEQ ID NO:1, previously disclosed and claimed in U.S. Pat. No. 5,559,212.
- An experiment was carried out using rectal tissue biopsies taken from six healthy HIV-uninfected volunteers. Three tissue explants were taken from each volunteer.
- Five liquid mixtures were formulated to test the prophylactic effect of ranpirnase against HIV. The mixtures were
- 105 TCID50 of HIV-1BaL together with 0.06 μg/mL ranpirnase
- 105 TCID50 of HIV-1BaL together with 0.6 μg/mL ranpirnase
- 105 TCID50 of HIV-1BaL together with 6 μg/mL ranpirnase
- 105 TCID50 of HIV-1BaL together with 66 μg/mL ranpirnase
- together with a control:
- 10 5 TCID50 of HIV-1BaL together with 0.00 μg/mL ranpirnase
- The fifteen tissue explants were arranged into five groups of three, with each group of three being incubated for two hours in a single one of these mixtures (one group is incubated in the control). The tissue explants were then washed multiple times and cultured at 37° C. and 5% CO2 for fourteen days, during which interval supernatant was collected on
Days -
- 90% RPMI 1640—445 mL,
- 10% Fetal Bovine Serum—50 mL, and
- 1% Antibiotic/Antimycotic—5.0 mL.
- The severity of HIV infection of the tissue explants was determined by assaying the supernatant for HIV-1 p24 antigen using the AlphaLISA platform. The efficacy endpoint was the tissue explant weight adjusted
Day 14 cumulative HIV-1 p24. As can be seen in all the Figures, increasing concentration of ranpirnase caused a dose-dependent reduction in HIV-1 p24 antigen in the tissue explants. The statistical significance p of the displayed data is shown in the Figures; whether the data are averaged or not, the results for 0.00 μg/mL, 0.06 μg/mL, and 0.6 μg/mL concentrations of ranpirnase are below the 5% level of significance. And, the results for 6.00 μg/mL and 66 μg/mL concentrations of ranpirnase are below the 1% level of significance where the results of each group of three tissue explants are averaged, and below the 0.1% level of significance where the results of each tissue explant is taken individually. - In each of the Figures, the standard error of the mean is also shown by the vertical lines shown by themselves in
FIG. 3 and superposed on the bars inFIGS. 1 and 2 . As would be expected, in instances wherein the level of significance is highly stringent (less than 1%) the standard error of the mean is smaller than in instances wherein the level of significance is less stringent (less than 5%). - It will be noted that this experiment was conducted using tissue explants from six individuals even though only five triplets of tissue explants were assayed after exposure to the identified mixtures of ranpirnase and HIV-1BaL and the control. This is because an additional triplet of tissue explants exposed to ranpirnase alone was subjected to an MTT assay in order to rule out the possibility that ranpirnase caused cellular toxicity.
- Hence, this experiment showed that tissue explants exposed to ranpirnase—and particularly to ranpirnase concentrations of 6 μg/mL and greater—developed increased resistance to HIV infection, i.e. that ranpirnase had a microbicidal effect.
- Advantageously, the topical pharmaceutical composition disclosed in the above-referenced parent patent application is used as a microbicide, and is topically applied to an individual who is to be protected. Further advantageously, the topical pharmaceutical composition can be applied to body regions that might be exposed to HIV during sexual intercourse The enzymatically-active ribonuclease can be ranpirnase. Alternatively, there is at least one other ribonuclease having enzymatic activities similar to that of ranpirnase, and this may be used instead of ranpirnase. For example, the “805 variant” (SEQ ID NO:2)is over 90% homologous to ranpirnase, in that the amino acid sequences of the two ribonucleases differ at only three positions (positions 11, 20, and 103) and has similar antiviral activities. Furthermore, it is known that the active site of ranpirnase is located at its N-terminal, and since the N-terminal amino acid sequences of ranpirnase and the '805 variant are identical, it follows that they will encode identical active sites. Thus, a person of ordinary skill in this art would expect the '805 variant to have the same prophylactic effect as ranpirnase has.
- Although this experiment was carried out by exposing rectal tissue explants to solutions containing ranpirnase, it is believed that the same results would be achieved by using another method to deliver ranpirnase to the tissue that may be exposed to HIV. This other method, a second preferred embodiment of the invention, is by using human microbiota to produce ranpirnase. An example of this mode of administration can be found at Gebhart et al., mBio, Vol. 6, Issue 2, pp. 1-13, (March/April 2015). The disclosure of this publication is incorporated herein by reference.
- For example, let it be assumed that mucosal tissues (e.g. the vagina, the rectum) are to be prophylactically protected from HIV. E. coli and Lactobacillus are part of the microbiota in those regions. Ranpirnase DNA can be transfected into E. coli or Lactobacillus (or both) and the thus-modified E. coli or Lactobacillus introduced into the subject. The modified E. coli or Lactobacillus would then infect the subject and thereby produce ranpirnase in the mucosal tissues involved. Alternatively, other bacteria could be used to prophylactically protect other tissues against other viral infections. For example, probiotic E. coli into which ranpirnase DNA had been transfected could be used to protect against viral infections of the digestive tract. Similarly-modified saprophytic Streptococcus could be delivered to protect a subject's external genitalia against HIV.
- A third preferred embodiment of the invention is suitable for use by women. In this third embodiment, an intravaginal ring 10 (
FIG. 4 ) of a suitably porous and biocompatible material (such as is described below) is impregnated with ranpirnase and inserted into the vagina, where the ranpirnase is dispensed. The ranpirnase may be mixed with other agents (e.g. dispersing agents). - Intravaginal rings are known and are used to dispense birth control drugs as well as dapivirine (a candidate microbicide now in clinical trials). An exemplary composition of such a ring is disclosed at Table 2 of Holt, et al., Antimicrobial Agents and Chemotherapy, Vol. 59, No. 7, pp. 3761-3770 (July, 2015), the disclosure of which is incorporated herein by reference.
- Although preferred embodiments have been described above, the invention is limited only by the following claims:
Claims (14)
1. A method of prophylactically protecting an individual from transmission of a sexually-transmitted infection, comprising the step of topically applying to the individual a topical pharmaceutical composition consisting essentially of a prophylactically effective concentration of an enzymatically-active ribonuclease and a viscous vehicle that does not unacceptably interfere with the enzymatic activity, wherein the infection is Human Papilloma Virus (HPV) or Herpesviridae.
2. The method of claim 1 , wherein the infection is HPV infection.
3. The method of claim 2 , wherein the infection is selected from the group consisting of anogenital warts, epidermodysplasia verrucciformis, Buschke-Lowenstein disease, Bowenoid papulosis, and dysplasia.
4. The method of claim 1 , wherein the infection is Herpesviridae infection.
5. The method of claim 1 , wherein the enzymatically-active ribonuclease is a member of the ribonuclease A superfamily.
6. The method of claim 5 , wherein the enzymatically-active ribonuclease is selected from the group consisting of ranpirnase and the '805 ranpirnase variant.
7. The method of claim 6 , wherein the enzymatically-active ribonuclease is ranpirnase.
8. The method of claim 5 , wherein the enzymatically-active ribonuclease is selected from the group consisting of Amphinase 2 and rAmphinase 2.
9. The method of claim 1 , wherein the vehicle is an aqueous vehicle.
10. The method of claim 9 , wherein the vehicle is a gel, a serum, or a lotion.
11. The method of claim 9 , wherein the vehicle is an approved sexual lubricant.
12. The method of claim 1 , wherein the vehicle is compatible with latex condoms.
13. The method of claim 1 , wherein the pharmaceutical contains between 0.06 and 66 μg of enzymatically-active ribonuclease per ml of vehicle.
14. The method of claim 13 , wherein the pharmaceutical contains between 6 and 66 μg of enzymatically-active ribonuclease per ml of vehicle.
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US14/462,520 US20160045574A1 (en) | 2014-08-18 | 2014-08-18 | Antiviral pharmaceutical for topical administration |
US14/793,920 US9642794B2 (en) | 2014-08-18 | 2015-07-08 | Antiviral pharmaceutical for topical administration |
US201662367050P | 2016-07-26 | 2016-07-26 | |
US15/582,133 US10835598B2 (en) | 2014-08-18 | 2017-04-28 | Prophylactic protection against viral infections, particularly HIV |
US17/064,215 US20210145960A1 (en) | 2014-08-18 | 2020-10-06 | Prophylactic protection against viral infections, particularly hiv |
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