Pharmaceutical composition for treating adverse
reactions by administering Spiegelmers
Technical fiedd of the invention
The invention relates to the use of an L-ribozyme for
producing a pharmaceutical composition, a
pharmaceutical composition containing said L-ribozyme
and a method for producing said pharmaceutical
composition.
Background of the invention and prior art
Aptamers are generally double-stranded D-nucleic acids,
which bind specifically to any target molecule,
similarly to an antibody/antigen reaction (Ellington,
A.D. et al,, Nature 346:819-822 (1990)). Specific
aptamers for a given target moleculs are isolated for
example by the SELEX process from nucleic acid
libraries (Tuerk, C. et al., Science 249:555-510
(1990)).
The purpose of aptamers, in the therapeutic range, is
among other things to bind and thereby inhibit
undesirable metabolic products. In "his connection we
need only mention for example oncogenic gene product..
A disadvantage in the therapeutic use of aptamers is
that they have unfavorable pharmacokinetics, i.e. are
very rapidly degraded, for example by endogenous
nucleases. Independently of this, aptamers are also
relatively small molecules, which are therefore
excreted relatively quickly via the kidneys.
spiegelmers are in essence aptamers, but differ from
them in that they are formed from L-nucleotides.
spiegelmers can be single-stranded or double-stranded.

Through the use of L-nucleotides, degradation by
endogenous nucleases is prevented and the
pharmacokinetics is thus considerably improved, i.e.
the residence time in the serum is prooonged. Thus, in
the reference Boisgard, R et al., Eur Journal of
Nuclear Medicine and Molecular imaging 32:470-477
(2005), it is described that nonfunctional Spiegelmers
are completely stable metabolically even for a period
of 2 hours. The diagnostic use of Spiegelmers is also
described in this reference, wherein the Spiegelmer is
coupled with a, for example radioactive, reporter
substance.
Specific Spiegelmers for a ~iven target molecule Can be
identified for example as described in the reference
Klussmann, S. et al,, Nat Biotechnol 14:1112-1115
(1996). Regarding the Spiegelmers and their possible
therapeutic applications, reference may also be made to
Vater, A. et al,, Curr Opin Drug Discov Devel 6:253-261
(2003).
In the therapeutic application of Spiegelmers, up to
now it has been assumed that Spiegelmers are not
immunogenic (WIotzka et al. I Proc Natl Acad Sci USA
99:8898-8902 (2002)). However, invesgigations that are
described in the present description show that, in an
organism, L-nucleic acids are by no means necessarily
free from side-effects. Hence it follows that when
using Spiegelmers there is certainly a nonnegligible
risk of an undesirable physiological side reaction, for
example an immune reaction and/or an undesirable
enzymatcc reaction with endogenous RNA (including a
regulatory RNA), on administranion to a patient. In
particular in the light of the negative experience with
the monoclonal antibody TGN1412 in the Phase 1 Clinical
trial and against the background that the residence
time of Spiegelmers, based on the relations mentioned
above, is comparatively very high, it would be

desirable to have an antidote to a Spiegelmer that: is
to be used, ready when administering the Spiegelmer, so
that if there is an undesirable physiological side
reaction the antidote can be administerec without delay
and the level of Spiegelmer in the Serum can be lowered
quickly.
From other contexts, namely the ribozyme-catalyzed
stereoselective Diels-Alder reaction, L-ribozymes are
known, for which reference may be made to Seelig, B. et
al., Angew.Chem. Int., 39:4576-4579 (2000) and Seelig,
B. et al., Angew. Chem. 112:4764-4768 (2000) .
Technical problem of the invention
The invention is therefore based on the problem of
providing an antidote for spiegelmers used
therapeutically.
Summary of the invention
For solving this technical problem. the invention
teaches the use of an L-ribozyme for producing a
pharmaceutical composition, wherein the L-ribozyme is
able to cleave an L-RNA in the region of a target
sequence of the L-RNA, and in particular for producing
a pharmaceutical composition for treating undesirable
physiological side reactions, in particular immune
reactions and/or undesirable enzymatic reactions of the
L-RNA with endogenous RNA (including a regulatory RNA),
owing to the administration of a therapeutic molecule
containing the L-RNA.
The invention is based firstly on the surprising
finding that Spiegelmers contrary to existing
assumptions are not necessarily free of adverse

reactions, but rather can be capable of cleaving
nucleic acids that occur naturally in an organism and
thus producing unforeseeable adverse reactions. The
invention is based on this finding, building on the
technical teaching of making L-ribozymes availabe,,
which specifically cleave a Spiegelmer that has been
administered and thus destroy its physiological
efficacy, in particular with respect to undesirable
side reaction.. Examples of Spiegelmers are:
Spiegelmer, NOXC89, NOXA42, NOXA50, NOXB11, NOXA12,
NOXE36, NOXF37 (all NOXXON AG), Spiegelmers from the
company Eli Lilly & Co., NU172 from the company ARCA
biopharma Inc., ARCHEMIX, ARC1905, ARC1779, ARC183,
ARC184, E10030, NU172, REG2, REG1 (all Archemix Corp.),
AS1411, AS140 (both Antisoma Research Ltd.), DsiRNA
from Dicerna Pharmaceuticals Inc,, FNA Aptamer BEXCORE
from BexCore Inc,, ELAN from the company Elan Corp Plc,
or Macugen. By administering such a ribozyme following
the observation of an undesirable side reaction on
administration of a Spiegelmer, the cause of the
undesirable side reaction can therefore be removed from
the metabolism rapidly, effectively and highly
selectively, and moreover at extremely low risk of
adverse reactions from the administration of the L-
ribozyme. The latter is based not only on the
construction of the L-ribozyme from L-nucleotides. but
additionally on the high selectivity of the L-ribozyme,
namely directed onto the target sequence of the
Spiegelmer. As a result, a highly effective and highly
selective antidote against a therapeutically used
Spiegelmer is obtained and undesirable side reactions
of the Spiegelmer can be countered effectively, rapidly
and without side-effects.
Basically against any RNA molecule, whether made up of
D- or L-nucleotides, it is possible to construct a
specific ribozyme, which cuts and thus cleaves a target
sequence of the RNA molecule. An essential property of

a ribozyme is thus the sequence-specific binding of the
ribozyme to the target sequence. However, this also
means that for any target sequence, a partial sequence
of a ribozyme can be prepared in such a way that the
partial sequence of the ribozyme, containing the
cleavage site, hybridizes to the target sequence.
Therefore, within the scope of the invention, it is not
expedient for only particular ribozyme partial
sequences to be defined structurally with respect to
particular target sequences. The target sequences and
ribozyme partial sequences given in the examples are
therefore only illustrations and a person skilled in
the art can readily determine the appropriate, namely
hybridizing ribozyme partial sequence for each given
target sequence of a Spiegelmer and synthesize the
ribozyme with the usual technical means on the basis of
the information on the ribozyme partial sequence.
Basically, the therapeutic molecule can be a
spiegelmer, or the L-RNA can be bound covalently to an
aptamer. This last-mentioned case may occur for example
in the case of an aptamer stabilized against nucleases.
Then the therapeutic benefit of the invention is that
by cutting the L-RNA, the aptamer is made accessible
for nucleases, so that finally even an aptamer that is
causing adverse reactions can be eliminated
comparatively quickly from the serum.
However, it is also possible that the L-ribozyme is
bound covalently to an aptamer or an antibody. In that
case the aptamer or the antibody can for example be
selected so that owing to the interactions of the
aptamer or of the antibody with cell surfaces, the
total construct of L-ribozyme and aptamer or antibody
is introduced into the cell.
Preferably the L-ribozyme is a hammerhead ribozyme.
Hammerhead ribozymes have a conserved region possibly

with a triplet GUH (H is net guanine preferably C) or
a doublet UH (H as above). Regarding the fermer,
reference may be made to Fig. 1. Regarding the latter,
reference may be made to Usman, N, et al,, The Journal
of Clinical Investigation, 106 (10):1197-1201 (2000).
Here, the nucleotides N' and N are any bases, which are
selected in the region of the stems I and III according
to the target sequence. Essentialy, the procedure for
constructing an L-ribozyme against a target sequence is
first to specify & target sequence, for example a
Spiegelmer, wherein said target sequence must contain
the triplet GUH or the doublet UH. Then on both ends of
a triplet GUH or of the doublet UH, typically in each
case 4-10 or 4-11, in particular 6-8 or 6-9,
nucleotides are added, whose sequences correspond to
the sequences of the target sequence. A copy of the
target sequence containing the triplet GUH or the
doublet UH is thus obtained, containing 11 to 23
nucleotides. Then the catalytic hammerhead sequence, as
shown in Fig. 1, is inserted between the two ends of
the copy. An example of a suitable catalytic hammerhead
sequence is thus:
5' -CUGANGAGN' CN' NNNNNGNCGAAAC-3' or
5' -CUGANGAGN' CN' NNNNNGNCGAAAN-3'
(N = any bases, wherein in Fig. 1, N and N' opposite
one another necessarily form identical or different
base pairs)
This is joined at the 3' -end to nucleotides in the
sequence complementary to the target sequence in the
5' -direction of the triplet GUH or doublet UH and at
the 5' -end to nucleotides in the sequence corresponding
to the target sequence in the 3' -direction of the
triplet GUH or doublet UH.

In a preferred embodiment the catalytic hammerhead
sequence is
5' -CUGANGAGNUCGGAAACGACGAAAC-3' Or
5' -CUGANGAGNUCGGAAACGACGAAAN-3''
(N = any bases, wherein in Fig. 1, H and. N' , which are
opposite to one another, necessarily form identical or
different base pairs)
Additionally, the sequence
3' - (N)4-6GGUAUAGAGUGCUGAAUCC-5'
can be established at the 5' -end of the catalytic
hammerhead sequence, sO that a hammerhead ribozyme is
obtained, which requires a comparatively low Mg-ion
concentration.
The pharmaceutical composition contains the L-ribozyme
in at least the dose that corresponds to the dose of
administration of the L-RNA, and preferably contains it
in a dose that corresponds to 2-10 times the dose of
administration of the L-RNA, relative to the moles or
number of molecules. An overdosage, compared with the
dose of the L-RNA, is recommended, to ensure that all
L-RNA to be eliminated is reacted. The absolute doses
envisaged according to the invention are based
strictly, in the stated relative proportions, or the
specified doses of the L-RNA and can therefore easily
be determined and established by a person skilled in
the art, knowing the specified doses for the L-RNA.
In a preferred embodiment of the invention the
pharmaceutical composition additionally contains a
nucleic acid, in particular a 5- tc 20-mer, which is
capable of the fusing-on of a double-stranded L-RNA in
the region of its target sequence. These are sequences

that hybridize to partial sequences that are adjacent
to the target sequence. As a result, GUC regions of the
L-RNA, which normally are not accessible for steric
reasons owing to the tertiary structure of the L-RNA,
are made accessible for the L-ribozyme.
The invention further relates to a pharmaceutical
composition containing an L-ribozyme for treating
undesirable physiological side reactions, in particular
immune reactions, due to the administration of a
therapeutic molecule containing the L-RNA.
With respect to the pharmaceutical composition, all the
above and subsequent details apply similarly.
Finally the invention relates to a method for producing
said pharmaceutical composition, wherein a sequence is
prepared and synthesized from L-nucleotides, which is
capable of cleaving a given sequence of L-
ribonucleotides, in particular containing the triplet
GUC with otherwise any sequences attached upstream and
downstream of the triplet, and wherein the L-ribozyme
is intended for administration in a pharmacologically
effective dose. Typically, the L-ribozyme is mixed with
pharmaceutical excipients and/or carriers.
Basically one or more physiologically compatible
excipients and/or carriers can be mixed with the L-
ribozyme and the mixture can be designed
pharmaceutically for local or systemic administration,
in particular oral, parenteral, for infusing into a
target organ, for injection (e.g. i.v., i.m,,
intracapsular or intralumbar), for application in tooth
pockets (space between tooth root and gum) and/or for
inhalation. The choice of additives and/or excipients
will depend on the selected dosage form. The
pharmaceutical preparation of the pharmaceutical
composition according to the invention can take place

in the usual manner. As counterions for ionic
compounds, for examp1e Mg++. Mn++ Ca++, CaCl+, NA+ K+
LI+ or cyclohexyaammonium, or Cl-, Br-, acetate,
trifluoroacetate, propionate, lactate, oxalate,
malonate, maleate, citrate, benzoate, salicylate,
putrescine, cadaverine, spermidine, spermine, etc. may
be considered. Suitable solid or liquid pharmaceutical
dosage forms are for example granules, powder, coated
tablets, tablets, (micro-) capsules, suppositories,
syrups, juices, suspensions, emulsions, drops or
solutions for injection (i.v., i.p., i.m., s.c)) or
nebulization (aerosols), dosage forms for dry powder
inhalation, transdermal systems, and preparations with
sustained release of active substance, for production
of which usual excipients find application, such as
carriers, disintegrate, binders, coating materials,
swelling agents, glidants or lubricants, tastants,
sweeteners and solubilizers. It is also possible to
encapsulate the active substance in preferably
biodegradable nanocapsules,, for example for making a
preparation for inhalation. As excipients, we may
mention for example magnesium carbonate, titanium
dioxide, lactose, mannitol and other sugars, talc,
lactoprotein, gelatin, starch, cellulose and
derivateses thereof, animal and vegetable oils such as
cod-liver oil, sunflower, peanut or sesame oil,
polyethylene glycols and solvents, such as sterile
water and monohydric or polyhydric alcohols, for
example glycerol. A pharmaceutical composition
according to the invention can be produced by mixing at
least one substance combination used according to the
invention ln a defined dose with a pharmaceutically
suitable and physiologically compatible carrier and
optionally further suitable active substances,
additives or excipients with a defined dose and
processing to the desired dosage form. Polyglycols
water and buffer solutions may be considered as
diluents. Suitable buffer substances are for example

N N' -dibenzylethylenediamine, diethanolamine,
ethyenediamine, N-methylglucamine, N-
benzylphenethylamine, diethylamine, phosphate, sodium
bicarbonate/ or sodium carbonate. However, it is also
possible to work without diluent. physiologically
compatible salts are salts with inorganic or organic
acids, for example lactic acid, hydrochloric acid,
sulfuric acid, acetic acid, citric acid, p-
toluenesulfonic acid, or with inorganic or organic
bases, for example NaOH, KOH, Mg(OH)2, diethanolamine,
ethylenediamine, or with amino acids, such as arginine,
lysine, glutamic acid etc. or with inorganic salts,
such as Cacl2, NaCl or free ions thereof, such as Ca2+,
Na+ Cl-, SO42- or corresponding salts and free ions of
Mg++ or Mn++ or combinations thereof. They are produced
according to standard methods. preferably a pH is
established between 5 and 9, especially between 6 and
8.
A variant of the invention, which comprises the use of
an L-riboyyme for producing a pharmaceutical
composition for treating or preventing diseases that
are associated with overexpression of at least. one
endogenous gene, wherein the L-ribozyme is capable of
cleaving a target sequence of an endogenous target D-
RNA coding for the gene, is important in its owu right.
Otherwise the above statements apply similarly. In this
connection, in another important variant of the above
aspect of the invention an L-ribozyme is used for
producing a pharmaceutical composition for treating or
preventing diseases that are associated with infection
of a mammal with a microorganism, wherein the L-
ribozyme is capable of cleaving a target sequence of a
target D-RNA coding for a gene of the microorganism.
Viruses, bacteria and fungiI among others, may be
mentioned as microorganisms that may be considered.
Basically the ribozyme can be used for the cleavage of
any microorganism with at least partially known gene

sequences, wherein regions of the gene sequences are
selected for the purpose of cleavage, which for example
attenuate or inhibit the activity of the microorganism
and/or its capacity for replication and/or attenuate or
inhibit binding to cell surfaces.
This variant makes use of the fact that L-ribozymes can
also be used for cleaving D-RNA, in particular mRNA or
regulatory RNA, for example, but not exclusively,
siRNA, microRNA, shRNA, ncRNA. tRNA, rRNA, etc. In this
way genes or proteins encoded by them can be inhibited.
This is of therapeutic benefit for all diseases that
are associated with the overexpression of particular
genes, compared with the expression in the non-diseased
organism
This variant has on the one hand the advantage that
cleavage of the target sequence takes place with very
high specificity and therefore there is also no other
interference with the regulatory system. Moreover,
adverse reactions, such as are associated for example
with the use of inhibitory D-nucleic acids, such as
siRNA, are reliably avoided.
The invention is explained in more detail below, on the
basis of figures and examples. The figures show:
Fig. 1: a minimal hammerhead ribozyme before (a. and
after binding to a target sequence (b),
Fig. 2: a comparative analysis of the reaction of L-
target with D-ribozyme on the one hand and of
D-target with L-ribozyme on the other hand as
a function of the MgCl2 concentration,
Fig. 3: a comparative analysis of the time dependence
of the reaction of L-target with D-ribozyme

on the one hand and of D-target with L-
ribozyme on the other hand at 10 mM MgCl2,
Fig. 4: a comparative analysis of the dependence on
MgCl2 concentration (1-25 mm) of the reaction
of L-target with L-ribozyme on the one hand
and of D-target with D-ribozyme on the other
hand at 10-fold L-ribozyme excess,
Fig. 5: a comparative analysis of the dependence on
MgCl2 concentration (0.1-1 mM) of the
reaction of L-target with L-ribozyme on the
one hand and of D-target with D-ribozyme on
the other hand at 10-fold L-ribozyme eXCESS,
Fig. 6: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and of D-target with D-
ribozyme on the other hand at 10 mM Mgcl2 and
at 10-fold L-ribozyme excess,
Fig. 7: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and of D-target with D-
ribozyme On the other hand at 0.1 mM MgCl2 and
at 10•fold L-ribozyme excess,
Fig. 8: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and of D-target with D-
ribozyme on the other hand at 1 mM MgC12 and
at 1-fold L-ribozyme excess,
Fig, 9: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and of D-target with D-
ribozytne on the other hand at 0.1 mM MgCl2 and
at 10-fold L-ribozyme deficit,

Fig 10: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and 0f D-target with D-
ribozyme on the other hand at 1 mM MgCl2 and
at 10-fold L-ribozyme deficit,
Fig. 11: a comparative analysis of the time dependence
of the reaction of L-target with L-ribozyme
on the one hand and of D-target with D-
ribozyme on the other hand at 5 mM MgCl2 and
at 10-fold L-ribozyme deficit, and
Fig. 12: testa on eleavage of L-target by L-ribozyme
in human serum.
Example 1: Cleavage assay
The activities of L-ribozymes and D-ribozymes were
measured in various conditions. The basic conditions
were as follows. 0.02 µM target RNA was incubated with
10 µ1 reaction mixture in the presence of 0.002 µM,
0.02 µM and 2 µM ribozyme in 50 mM Tris-Hc1 buffer, pH
7.5, at 200C for 2 hours (ribozymes/target ratio
therefore 10:1, 1:1 and 1:10). Before the reaction,
target RNA and ribozyme were denatured for 2 minutes at
70°C and cooled slowly (l°C/min) in the heating unit to
25°C. The influence of the Mg2+ ions at concentration
from 0.1 to 25 mM was investigated. Cleavage products
were separated on 20% polyacrylamide gel
electrophoresis in the presence of 8 M urea in 0.09 M
Tris-borate buffer, pH 8.3. The fluorescence was
analyzed on Phosphoimager Fuji Film FLA 5100. The data
were obtained with the program Fuji Analysis Program.
Diagrams were prepared with Excel.

Example 2: Preparation of the target sequences and
ribozymes
The following were prepared as target sequences by way
of contract synthesis by the company ChemGenes
Corporation, Wilmington, USA:
Seq-ID 1: 5' -FAM-ACAGUCGGUCGCC-3'
(RNA, both with D-nucleotides and with L-nucleotides)
and
Seq-ID 2: 5' -FAM-ACAGTCGGTCGCC-3'
(DNA, both with D-nucleotides and with L-nucleotides).
The synthesis products had a purity of over 90%.
As ribozyme sequences, depending on the target
sequences, the variable regions of a hammerhead
ribozyme were selected by the triplet GUC and the
following ribozyme sequences were prepared by the
company ChemGenes Corporation, Wilmington, USA:
Seq-ID 3: 5' -FAM-GGCGACCCUGAUGAGGCCGAAAGGCCGAAACUGU-3'
(RNA, both with D-nucleotides and with L-nucleotides)
The synthesis products had a purity of over 85%.
All synthesis products were labeled with fluorescein at
the 5' -end.
Example 3: Interactions of L-nucleic acids with D-
nucleic acids
Fig. 2 shows the concentration, dependence of the
cleavage of a D-target by an L-ribozyme and vice versa
C is the control (L-target + L-ribozyme), tracks 1 to 5
are the various Mgcl2 concentration, given in the

diagram (0-25 mM) for target without ribozyme, tracks 6
to 9 0.2 µM target with 2 µM ribozyme.
It can be seen that D-ribozyme does not cleave L-
target, but conversely a notable reaction certainly
occurs. This means that for example Spiegellmers,
consisting of L-nucleotides, in addition to their
action as specific aptamer for a given 3-D structure,
contrary to the existing notion might certainly be able
to engage in further physiological interactions, for
example as ribozyme.
Hence it follows that Spiegelmers pose the risk of an
undesirable side-effect on administration to an
organism.
However, it also follows that L-ribozymes can be used
for the cleavage of endogenous D-RNA, leading to
therapeutically desired inhibition of the gene or
protein coded by the D-RNA, for example mRNA.
Fig. 3 shows that the proportion of; cleavage products
of the D-target by an L-ribozyme increases with time
and is always significantly above the proportion of
cleavage products of the L-target (track c: control, as
above, tracks 1 to 10, times 0 to 256 min of the
diagram).
Example 4: Cleavage of an L-target by L^ribozymes
It Can be seen from Figs. 4 to 11 that an L-ribozyme
effectively cuts an L-target with corresponding target
sequence in all usual conditions, and moreover with
turnover rates that at least correspond to those of a
D-ribozyme with a D-target.

Fig. 12 provides evidence that the cleavage of an L-
target by an L-ribozyme also functions effectively
under the conditions of human serum.

WECLAIM:

1. The use of an L-ribozyme for producing a
pharmaceutical composition.
2. The use as claimed in claim 1, characterized in
that the L-ribozyme is capable of cleaving an L-
RNA in the region of a target sequence of the L-
RNA.
3. The use of an L-ribozyme, which is capable of
cleaving an L-RNA in the region of a target
sequence of the L-RNA, for producing a
pharmaceutical composition for treating
undesirable physiological side reactions due to
the administration of a therapeutic molecule
containing the L-RNA.
4. The use of an L-ribozyme for producing a
pharmaceutical composition for treating or
preventing diseases that are associated with
overexpression of at least one endogenous gene,
characterized in that the L-ribozyme is capable of
cleaving a target sequence of an endogenous target
D-RNA coding for the gene.
5. The use as claimed in claim 3, characterized in
that the therapeutic molecule consists of the L-
RNA, in particular is a double-stranded L-RNA, for
example a Spiegelmer.
6. The use as claimed in claim 3, characterized in
that the therapeutic molecule contains an aptamer
bound covalently to the L-RNA or antibody bound
covalently thereto.
7. The use as claimed in one of claims 3 and 5 to 6
characterized in that the pharmaceutical

composition contains the L-ribozyme in at least
the dose corresponding to the dose of
administration of the L-RNA, preferably contains
it in a dose that corresponds to 2 to 100 times,
preferably 2 to 20 times the dose of
administration of the L-RNA.
8. The use as claimed in one of claims 3 to 7,
characterized in that the L-rbbozyme is a
hammerhead ribozyme.
9. The use as claimed in one of claims 3 to 8,
characterized in that the pharmaceutical
composition additionally contains a nucleic acid,
in particular a 5- to 20-mer, which is capable of
the fusing-on of a double-stranded D-RNA or L-RNA
in the region of the targtt sequence.
10. A pharmaceutical composition containing an L-
ribozyme for treating undesirable physiological
side reactions, due to the administration of a
therapeutic molecule containing the L-RNA.
11. A pharmaceutical composition containing an L-
ribozyme for treating or preventing diseases that
are associated with overexpression of at least one
endogenous gene, characterized in that the L-
ribozyme is capable of cleaving a target sequence
of an endogenous target D-RNA acding for the gene.
12. A method of production of a pharmaceutical
composition as claimed in claim 10 or 11,
characterized in that a sequence of L-nucleotides
is prepared and synthesized, which is capable of
cleaving a given sequence of L-ribonucleotides or
a given sequence of D-ribonucleotides, and in that
the L-ribozyme is prepared for administration in a
pharmacologically effective dose.

The method as claimed in claim 12, characterized
in that the L-ribozyme is mixed with
pharmaceutical excipients and/or carriers.

The invention relates to the use of an L-ribozyme, which is capable of
splitting an L-RNA in the region of a target sequence of the L-RNA, in order
to produce a pharmaceutical composition for treating undesired
physiological adverse reactions due to the administration of a therapeutic
molecule containing the L-RNA. Alternatively, an endogenous target RNA
may also be split by the L-ribozyme.