US20220125890A1 - Treatment and detection of inherited neuropathies and associated disorders - Google Patents

Treatment and detection of inherited neuropathies and associated disorders Download PDF

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US20220125890A1
US20220125890A1 US17/517,227 US202117517227A US2022125890A1 US 20220125890 A1 US20220125890 A1 US 20220125890A1 US 202117517227 A US202117517227 A US 202117517227A US 2022125890 A1 US2022125890 A1 US 2022125890A1
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sord
gene
subject
mutation
sorbitol
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Stephan L. Zuchner
Adriana Rebelo
Andrea CORTESE
Rong Grace ZHAI
David N. HERRMANN
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UCL Business Ltd
University of Miami
University of Rochester
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UCL Business Ltd
University of Miami
University of Rochester
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Priority to US17/719,580 priority patent/US20230293642A9/en
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Assigned to UNIVERSITY OF MIAMI reassignment UNIVERSITY OF MIAMI ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZHAI, Rong Grace, REBELO, Adriana, ZUCHNER, Stephan L.
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Definitions

  • the present disclosure relates to methods of detecting and treating inherited neuropathy.
  • CMT Charcot-Marie-Tooth disease
  • Distal hereditary motor neuropathy represents a form of CMT2 in which the burden of disease falls predominantly or exclusively on motor nerves (Rossor, Tomaselli, and Reilly 2016).
  • a similar condition includes ALS4 (juvenile dHMN+brisk reflexes as sign of upper motoneuron involvement).
  • CMT1 for which over 90% of cases have mutations in known genes, only 20 to 30% of CMT2 and distal HMN patients receive a genetic diagnosis (Fridman et al. 2015).
  • the disclosure provides a method of treating and/or detecting inherited neuropathy.
  • the method comprises detecting the presence of a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from a subject.
  • the SORD mutation is a DNA variant classified as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria.
  • the method comprises diagnosing the subject with inherited neuropathy when the presence of a mutation in the SORD gene is detected.
  • the method comprises administering to the subject a composition that comprises an agent selected from the group consisting of an aldose reductase inhibitor; an aldose reductase antisense oligonucleotide; a polynucleotide that encodes a SORD peptide; a SORD peptide; an agent that blocks expression of a mutant SORD gene; and an agent that corrects the mutation in SORD gene.
  • an agent selected from the group consisting of an aldose reductase inhibitor; an aldose reductase antisense oligonucleotide; a polynucleotide that encodes a SORD peptide; a SORD peptide; an agent that blocks expression of a mutant SORD gene; and an agent that corrects the mutation in SORD gene.
  • the method comprises administering to the subject Alrestatin, Epalrestat, Diepalrestat, Fidarestat, Imirestat, Lidorestat, Minalrestat, Ponalrestat, Ranirestat, Salfredin B 11 , Sorbinil, Tolrestat, Zenarestat, or Zopolrestat (or a combination thereof).
  • the method comprises administering to the subject an aldose reductase antisense oligonucleotide; a polynucleotide that encodes a SORD peptide; an agent that blocks expression of a mutant SORD gene; an agent that corrects the mutation in SORD gene; or a combination of any of the foregoing.
  • the method comprises administering to the subject a SORD peptide. Administration of a combination of any of the foregoing is also contemplated.
  • the method comprises measuring sorbitol levels in a sample from the subject.
  • an (i) aldose reductase inhibitor e.g., Alrestatin, Epalrestat, Diepalrestat, Fidarestat, Imirestat, Lidorestat, Minalrestat, Ponalrestat, Ranirestat, Salfredin B 11 , Sorbinil, Tolrestat, Zenarestat, and/or Zopolrestat
  • an aldose reductase antisense oligonucleotide a polynucleotide that encodes a SORD peptide, an agent that blocks expression of a mutant SORD gene, and/or an agent that corrects the mutation in a SORD gene
  • a SORD peptide for the treatment of inherited neuropathy or use in the preparation of a medicament for treatment of inherited neuropathy
  • SORD sorbitol dehydrogenase
  • the disclosure further provides a method of characterizing a neuropathy in a mammalian subject, the method comprising measuring the level of sorbitol in a subject suffering from a neuropathy, wherein a sorbitol level of greater than about 10 g/L indicates that the neuropathy is associated with a mutation in the sorbitol dehydrogenase (SORD) gene.
  • SORD sorbitol dehydrogenase
  • the disclosure also provides a method of evaluating the efficacy of a treatment for an inherited neuropathy in a subject, the method comprising administering to the subject an agent selected from the group consisting of an aldose reductase inhibitor (e.g., Alrestatin, Epalrestat, Diepalrestat, Fidarestat, Imirestat, Lidorestat, Minalrestat, Ponalrestat, Ranirestat, Salfredin B 11 , Sorbinil, Tolrestat, Zenarestat, and/or Zopolrestat), an aldose reductase antisense oligonucleotide, a polynucleotide that encodes a SORD peptide, a SORD peptide, an agent that blocks expression of a mutant SORD gene, and an agent that corrects the mutation in SORD gene (or a combination of any of the foregoing); and measuring the level of sorbitol in a subject.
  • an aldose reductase inhibitor e.g.,
  • each feature or embodiment, or combination, described herein is a non-limiting, illustrative example of any of the aspects of the disclosure and, as such, is meant to be combinable with any other feature or embodiment, or combination, described herein.
  • each of these types of embodiments is a non-limiting example of a feature that is intended to be combined with any other feature, or combination of features, described herein without having to list every possible combination.
  • Such features or combinations of features apply to any of the aspects of the invention.
  • FIGS. 1A-F SORD gene and pedigrees. Biallelic mutation in SORD cause autosomal recessive dHMN/CMT2.
  • FIG. 1A Representative pedigrees of dHMN/CMT2 families carrying biallelic mutations in SORD. The squares indicate males and the circles females. The diagonal lines are used for deceased individuals. Patients are indicated with filled shapes.
  • FIG. 1B Schematic diagram showing all exons, introns and untranslated regions (UTRs) of SORD on the basis of NCBI Reference Sequence: NM 003104.6. The gray and white boxes represent the coding sequence and UTRs of SORD, respectively.
  • FIG. 1C Distribution of mutation across SORD protein domains.
  • FIG. 1D SORD protein orthologs alignments showing that the four missense substitutions identified in dHMN/CMT2 families in this study are located at highly conserved residues across species from humans to elephants.
  • FIGS. 1E and 1F Magnification the nucleotide sequence of a highly homologous region in exon 7 in SORD (reverse strand) and SORD2P (forward strand).
  • Nucleotides differing in SORD2P from SORD are indicated with an arrow, including a FIG. 1C deletion in SORD2P.
  • Representative electropherograms shows that in SORD the c.757delG; p.(Ala253GlnfsTer27) variant found in homozygous state in dHMN/CMT2 patients and heterozygous state in available patents (right box, upper plot) is absent in biallelic state from healthy controls (right box, lower plot), but it is fixated in SORP2P (left box, lower plot).
  • FIGS. 2A-C Decreased SORD expression and sorbitol accumulation in patients fibroblasts.
  • FIG. 2A Schematic representation of the two-step polyol pathway converting glucose to fructose.
  • the graphs show the mean ⁇ s.d. and data distribution (dots).
  • a two-tailed t-test was performed to compare SORD encoded protein ( FIG. 2B ) or sorbitol level ( FIG. 2C ) across groups. Statistical significance is indicated as *, ** or *** if P-value ⁇ 0.05, ⁇ 0.01 or ⁇ 0.001, respectively. All experiments were repeated independently twice with similar results.
  • FIGS. 3A-F Loss of Drosophila Sord2 causes age-dependent synaptic degeneration.
  • FIG. 3A 3D structure of Drosophila visual system showing the lamina, medulla, and lobula. The xy- and xz-planes showing the photoreceptor terminals and lamina neurons are indicated.
  • FIG. 3B Lamina of yw control fly at 2 DAE. The organized lamina cartridges and columnar photoreceptor neurons are shown in the xy-plane and xz-plane, respectively.
  • FIG. 3C Laminae of Sodh2 MB01265/MB01265 homozygous flies at 2 DAE and 10 DAE.
  • FIG. 3D Quantification of the vacuole number, size, and BRP intensity. A total of 3 laminae of each group were quantified. Data are presented as mean ⁇ s.d. Statistical analysis was performed using Two-Way ANOVA followed by post-hoc Tukey's multiple comparison test. *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001. ( FIGS.
  • FIGS. 4A-G Treatment with aldose reductase inhibitors Epalrestat and Ranirestat decrease sorbitol level and restore function.
  • Sorbitol level as measured by UPLC from brain/head homogenates and normalised to protein concentration from wild-type (yw, empty circle dots), Sodh2 MB01265/MB01265 (full circle dots) and neuron-specific knock-down of Sodh1 and Sodh1 by RNAi (square dots) Drosophilae at 10 days after eggs enclosure.
  • Sodh2 Mimic and Sodh1 and Soh2 RNAi Drosophilae were fed with either 80 ⁇ M Epalrestat, 80 ⁇ M Ranirestat or DMSO. The graphs show the mean ⁇ s.d. A two-tailed t-test was performed to compare sorbitol level.
  • FIG. 4D-4F Laminae of Sodh2 MB01265/MB01265 homozygous flies at 10 DAE and 40 DAE fed with DMSO ( FIG. 4D ), 80 ⁇ M Epalrestat ( FIG. 4E ), or 80 ⁇ M Ranirestat ( FIG. 4F ).
  • Arrowheads indicate the lamina vacuoles. Boxes indicate higher magnification areas of the lamina. The intensity of BRP is indicated. Dotted lines indicate the area of lamina vacuoles. Scale bar: 30 ⁇ m.
  • FIG. 5 Pedigrees of families carrying biallelic mutations in SORD.
  • the squares indicate males and the circles females.
  • the diagonal lines are used for deceased individuals. Patients are indicated with filled shapes.
  • FIGS. 6A-B Double knockdown of Drosophila Sodh1 and Sodh2 lead to age-dependent synaptic degeneration.
  • FIG. 6A Laminae of Sodh1 and Sodh2 double knockdown homozygous flies at 2 DAE and 10 DAE. Arrowheads indicate the lamina vacuoles. Boxes indicate higher magnification areas of the lamina. The intensity of BRP is indicated. Dotted lines indicate the area of lamina vacuoles. Scale bar: 30 ⁇ m.
  • FIG. 6B Quantification of the vacuole number, size, and BRP intensity. A total of 3 laminae of each group were quantified. Data are presented as mean ⁇ s.d. Statistical analysis was performed using Two-Way ANOVA followed by post-hoc Tukey's multiple comparison test. *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001.
  • FIG. 7 Treatment with aldose reductase inhibitors Epalrestat and Ranirestat restore locomotor function in Sodh1 and Sodh2 double knockdown flies.
  • Locomotor activity of control flies (yw) feeding with DMSO dots, first data point from the left for each DAE point indicated), or flies with neuronal specific knockdown of Sodh1 and Sodh2 feeding with DMSO (squares, second data point from the left for each DAE point indicated), 80 ⁇ M Epalrestat (squares, third data point from the left for each DAE point indicated), or 80 ⁇ M Ranirestat (squares, forth data point from the left for each DAE point indicated).
  • n 10 in each group. Data are presented as mean ⁇ s.d.
  • Statistical analysis was performed using Two-Way ANOVA followed by post-hoc Tukey's multiple comparison test. ***P ⁇ 0.001, ****P ⁇ 0.0001.
  • FIG. 8 An illustration of an exemplary expression vector encoding the SORD peptide (pAAV-SORD).
  • FIG. 9 An exemplary complete AAV vector DNA sequence including the SORD coding sequence (pAAV-SORD) (SEQ ID NO: 1).
  • FIG. 10 SORD primer sequences and thermocycling conditions.
  • PCR polymerase chain reaction
  • Fw forward
  • Rv reverse.
  • FIG. 11 Clinical features of patients with hereditary neuropathy and carrying biallelic mutations in SORD.
  • FIG. 12 Clinical features of patients affected by hereditary neuropathy and carrying the biallelic mutations in SORD. Categorical data are expressed as N (%) if data is available in all individuals or N/number individuals considered (%). Continuous variables are expressed as mean ⁇ standard deviation (min-max). CMT, Charcot-Marie-Tooth, dHMN, distal hereditary motor neuropathy.
  • FIG. 13 Fasting sorbitol level in serum from ten unrelated healthy controls and ten patients carrying biallelic p.Ala253GlnfsTer27 mutations in SORD.
  • the graphs show the mean s.d. and data distribution (dots), and the p-value of two-tailed t-tests comparing SORD protein and sorbitol levels across groups—* p ⁇ 0.05, ** p ⁇ 0.01, and *** p ⁇ 0.001. All experiments were twice repeated independently.
  • FIGS. 14A-14C Exemplary vector design for SORD gene replacement therapy.
  • FIG. 14A AAV-9 packaged vector design for a SORD gene replacement therapy.
  • CB7 promotors have been shown to be effective in driving high expression, followed by the SORD cDNA (NCBI Reference Sequence: NM 003104.6), a Posttranscriptional Regulatory Element (WPRE) to further enhance expression and target specificity, and the transcription termination poly(A) element. Further origin of replication (pUC-ori) and ITR sequences (inverted terminal repeat).
  • FIG. 14B SORD cDNA sequence.
  • FIG. 14C SORD polypeptide sequence.
  • FIGS. 15A-15D Significant knock-down of aldose reductase (AR) (AKR1B1 gene) via an antisense oligonucleotide (ASO) (AR 1A, (SEQ ID NO: 22)).
  • ASO antisense oligonucleotide
  • FIG. 15A Targeting ASO (AR 1A) sequence and ASO-S scrambled sequence (AR-S 1A, (SEQ ID NO: 47)) are shown in FIG. 15A .
  • FIG. 15B shows the modifications to the nucleotide backbone of the ASOs. This was carried out in a SORD patient fibroblast and control fibroblasts and normalized to ⁇ -tubulin and measured via Western blot ( FIGS. 15C-15D ). A further control is a scrambled version of the ASO-S (AR-S 1A) exhibiting random nucleotides was used ( FIG. 15C ).
  • FIG. 17 A table of antisense oligonucleotide (ASO) sequences an target sites in Homo sapiens aldo-keto reductase family 1 member B (AKR1B1), exon targets only.
  • ASO antisense oligonucleotide
  • the disclosure provides a method of detecting and/or treating inherited neuropathy and related inherited conditions.
  • Inherited (or hereditary) neuropathies include, but are not limited to Charcot-Marie-Tooth disease (CMT), hereditary motor and sensory neuropathy, hereditary motor neuropathy, distal hereditary motor neuropathy (dHMN), axonal neuropathies, intermediate neuropathies, and amyotrophic lateral sclerosis type ALS4.
  • CMT Charcot-Marie-Tooth disease
  • dHMN distal hereditary motor neuropathy
  • axonal neuropathies axonal neuropathies
  • intermediate neuropathies intermediate neuropathies
  • the disclosure provides a method wherein the presence of a mutation in the sorbitol dehydrogenase (SORD) gene is detected in a sample from a subject.
  • the mutation may be detected by examining the DNA sequence of the gene, examining RNA, or examining proteins with mutations that result in some loss of function.
  • SORD Sorbitol dehydrogenase gene
  • SORD encodes sorbitol dehydrogenase, an enzyme which converts sorbitol to fructose. It belongs to the two-step polyol pathway previously identified as pivotal to nerve damage in hyperglycemic condition of diabetes. Forty-two cases of CMT across different ethnicities were identified as carrying a nonsense mutation in SORD, c.757delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state.
  • the method comprises detecting the SORD gene mutation 753delG; p.(Ala253GlnfsTer27), c.757delG; p.Ala253GlnfsTer27, c.28C>T; p.Leu10Phe, c.316_425+165del; p.Cys106Ter, c.329G>C; p.Arg110Pro, c.298C>T; p.Arg100Ter, c.295C>T; p.Arg299Ter, c.964G>A; p.Val322Ile, c.458C>A; p.Ala153Asp; a deletion of individual or multiple coding exons or the entire SORD gene via a copy number variation; or any protein truncating mutation and/or mutation that leads to a “loss of function” or a hypomorphic function of the protein.
  • the SORD mutation is detected using DNA sequencing methods such as whole exome sequencing, whole genome sequencing (WGS) and/or next-generation sequencing (NGS), allele specific oligonucleotides, polymerase chain reaction (PCR), quantitative or real-time PCR (qPCR), multiplex PCR, nested PCR, Amplification Refractory Mutation System (ARMS) PCR, Multiplex ligation-dependent probe amplification (MLPA), Denaturing gradient gel electrophoresis (DGGE), Single-Strand Conformation Polymorphism (SSCP), Protein Truncation Test (PTT), RFLP, DNA microarray, RNA-seq, using CRISPR-based mutation detection (e.g., CRISPR-Chip, Hajian et al., Nature Biomedical Engineering 3, 427-437 (2019)) or other DNA or RNA mutation detection methods suitable for mutation detection.
  • CRISPR-based mutation detection e.g., CRISPR-Chip, Hajian et al., Nature Biomedical
  • the SORD mutation is detected by examining proteins using western blotting (immunoblot), High-performance liquid chromatography (HPLC), Liquid chromatography-mass spectrometry (LC/MS), antibody dependent methods such as enzyme-linked immunosorbent assay (ELISA), protein immunoprecipitation, protein immunostaining, protein chip methods or other protein detection methods suitable for mutation detection.
  • western blotting immunoblot
  • HPLC High-performance liquid chromatography
  • LC/MS Liquid chromatography-mass spectrometry
  • ELISA enzyme-linked immunosorbent assay
  • protein immunoprecipitation protein immunostaining
  • protein chip methods or other protein detection methods suitable for mutation detection.
  • the method further comprises measuring sorbitol levels in a sample of the subject.
  • Methods of measuring sorbitol include, e.g., enzymatic assays, fluorimetric assays, chromatography-based methods, and spectroscopy-based methods.
  • An exemplary method of sorbitol measurement is provided in the Examples.
  • the disclosure further provides a method of characterizing a neuropathy (e.g., inherited neuropathy) and related conditions involving a SORD mutation.
  • the method comprises measuring sorbitol levels in a biological sample of a subject suffering from a neuropathy.
  • the method comprises detecting increased levels of sorbitol in the biological sample.
  • creased levels of sorbitol is meant, e.g., sorbitol levels above about 10 mg/L.
  • SORD-related neuropathy leads to high levels of sorbitol in patients, as described in the Examples and FIG. 13 .
  • the method comprises a treatment step comprising administering to the subject an agent selected from the group consisting of an aldose reductase inhibitor; an aldose reductase antisense oligonucleotide; a polynucleotide that encodes a SORD peptide; a SORD peptide; an agent that blocks expression of a mutant SORD gene; and an agent that corrects the mutation in SORD gene.
  • an agent selected from the group consisting of an aldose reductase inhibitor; an aldose reductase antisense oligonucleotide; a polynucleotide that encodes a SORD peptide; a SORD peptide; an agent that blocks expression of a mutant SORD gene; and an agent that corrects the mutation in SORD gene.
  • the disclosure provides a method comprising identifying a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from a subject before or after a step of measuring sorbitol levels in the subject.
  • the method may be used to confirm a diagnosis of inherited neuropathy.
  • the disclosure provides a method for identifying a SORD mutation that is pathogenic, the method comprising measuring sorbitol levels in a subject comprising a mutation in the SORD gene. The presence of increased sorbitol levels (e.g., greater than about 10 mg/L) indicates that the SORD mutation is pathogenic.
  • the method may be used to evaluate the efficacy of a treatment for an inherited neuropathy in a subject.
  • the method comprises administering a therapy to the subject, then measuring sorbitol levels in a biological sample.
  • a decrease in sorbitol levels compared to the level of sorbitol observed pre-treatment e.g., a reduction of sorbitol levels below about 10 g/L indicates an improvement in the subject's condition.
  • the materials and methods described herein may also characterize patient compliance in taking medication for treatment of SORD-related inherited neuropathies or monitor the success of candidate therapeutics in clinical trials.
  • the sample may be any biological sample taken from the subject, including, but not limited to, any tissue, cell, or fluid (e.g., blood, plasma, serum, or urine) which can be analyzed for a trait of interest, such as the presence or amount of a nucleic acid (e.g., SORD mRNA), a protein (e.g., SORD protein), or sorbitol.
  • a nucleic acid e.g., SORD mRNA
  • a protein e.g., SORD protein
  • sorbitol sorbitol
  • the biological sample is a plasma, serum, saliva, urine, or skin sample.
  • a “subject” as referred to herein, can be any mammal, such as humans.
  • Animals of agricultural importance, such as bovine, equine, and porcine animals, are contemplated, as well as animals important as domestic pets, including canines and felines; animals important in research, including rodents and primates; and large endangered species and zoo animals such as primates, felines, giraffes, elephants, rhinos.
  • the method comprises treating the subject by administering to the subject a composition that comprises one or more aldose reductase inhibitors.
  • the aldose reductase inhibitor is Alrestatin, Epalrestat, Diepalrestat, Fidarestat, Imirestat, Lidorestat, Minalrestat, Ponalrestat, Ranirestat, Salfredin B 11 , Sorbinil, Tolrestat, Zenarestat, or Zopolrestat.
  • Aldose reductase inhibitors are reviewed in Expert Opin Ther Pat. 2019; 29(3):199-213; Chatzopoulou et al., Expert Opin Ther Pat. 2012; 22(11):1303-23 (incorporated by reference in their entirety).
  • enzyme replacement therapy is employed, and a SORD peptide is administered to the subject.
  • the therapy supplements SORD peptide levels where endogenous SORD levels are inadequate or absent.
  • An exemplary SORD peptide is provided in SEQ ID NO: 46.
  • the disclosure contemplates use of a peptide that comprises at least 80%, at least 85%, at least 90%, at least 95%, or 100% identity to SEQ ID NO: 46.
  • the method comprises administering to the subject a polynucleotide (e.g., an aldose reductase anti sense oligonucleotide, a polynucleotide that encodes the SORD peptide/protein, an agent that blocks expression of a mutant SORD gene, and/or an agent that corrects the mutation in SORD gene).
  • a polynucleotide e.g., an aldose reductase anti sense oligonucleotide, a polynucleotide that encodes the SORD peptide/protein, an agent that blocks expression of a mutant SORD gene, and/or an agent that corrects the mutation in SORD gene.
  • Polynucleotides are typically delivered to a host cell via an expression vector, which includes the regulatory sequences necessary for delivery and expression, although use of expression vectors are not required in the context of the disclosure.
  • the constructs described herein include a promoter (e.g., cytomegalovirus (CMV) promoter or CB7 promoter), a protein coding region (optionally with non-coding (e.g. 3′-UTR) regions that facilitate expression), transcription termination sequences, and/or regulator elements sequences (e.g., Posttranscriptional Regulatory Element (WPRE), poly(A) element, origin of replication (pUC-ori) and/or ITR sequences (inverted terminal repeat)).
  • a promoter e.g., cytomegalovirus (CMV) promoter or CB7 promoter
  • a protein coding region optionally with non-coding (e.g. 3′-UTR) regions that facilitate expression
  • transcription termination sequences e.g., cytomegalovirus (CMV) promoter or CB7 promoter
  • regulator elements sequences e.g., Posttranscriptional Regulatory Element (WPRE), poly(A) element, origin of replication (pUC-ori)
  • the Cre-loxP system may be utilized to express a peptide of interest (e.g., a SORD peptides, optionally in a specific tissue of interest).
  • Expression vectors may be viral-based (e.g., retrovirus-, adenovirus-, or adeno-associated virus-based) or non-viral vectors (e.g., plasmids).
  • Non-vector based methods e.g., using naked DNA, DNA complexes, etc.
  • the vector is a viral vector, such as a lentiviral vector or baculoviral vector, and in various preferred embodiments the vector is an adeno-associated viral vector (AAV).
  • AAV adeno-associated viral vector
  • the expression vector may be based on any AAV serotype, including AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, AAV-11, AAV-12, or AAV-13.
  • Polynucleotides also may be delivered via liposomes, nanoparticles, exosomes, microvesicles, hydrodynamic-based gene delivery, or via a “gene-gun.”
  • Titers of AAV to be administered in methods of the disclosure will vary depending, for example, on the particular AAV, the mode of administration, the treatment goal, the individual, and the cell type(s) being targeted, and may be determined by methods known in the art. Titers of AAV may range from about 1 ⁇ 10 6 , about 1 ⁇ 10 7 , about 1 ⁇ 10 8 , about 1 ⁇ 10 9 , about 1 ⁇ 10 10 , about 1 ⁇ 10 11 , about 1 ⁇ 10 12 , about 1 ⁇ 10 13 to about 1 ⁇ 10 14 or more DNase resistant particles (DRP) per ml. Dosages may also be expressed in units of viral genomes (vg).
  • DNase resistant particles DNase resistant particles
  • a polynucleotide that encodes a SORD peptide is administered to the subject.
  • the amino acid sequence of SORD is provided as SEQ ID NO: 46 ( FIG. 14C , NCBI Reference Sequence: NP 003095.2).
  • the polynucleotide used in the method optionally encodes the amino acid sequence of SEQ ID NO: 46 or a sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to the amino acid sequence of SEQ ID NO: 46 (which retains the function of SORD).
  • the polynucleotide comprises SEQ ID NO: 45 ( FIG.
  • FIGS. 8 and 14A Exemplary expression vectors comprising a polynucleotide encoding the SORD peptide are illustrated in FIGS. 8 and 14A .
  • the polynucleotide in at least one aspect of the disclosure, comprises the nucleic acid sequence shown in FIG. 9 (SEQ ID NO: 1), which corresponds to the sequence of an AAV vector comprising a polynucleotide encoding SORD.
  • the method comprises administering to the subject an agent that blocks expression of a mutant SORD gene.
  • An agent that blocks expression of a mutant SORD gene refers to an agent that interferes with expression of a SORD gene so that SORD gene expression and/or SORD protein levels are reduced compared to basal/wild-type levels. It will be appreciated that “blocking” expression of a mutant SORD gene does not require 100% abolition of expression and SORD production; any level of reduced expression of aberrant SORD may be beneficial to a subject.
  • Exemplary agents include, but are not limited to, antisense oligonucleotides (ASO), short hairpin RNA (shRNA), small interfering RNA (siRNA), or micro RNA (miRNA).
  • the method comprises administering to the subject an aldose reductase antisense oligonucleotide which targets the aldose reductase sequence such that expression of the enzyme is blocked.
  • An aldose reductase, aldo-keto reductase family 1 member B (AKR1B1) is encoded by SEQ ID NO: 48 (NCBI Reference Sequence: NM 001628).
  • An aldose reductase antisense oligonucleotide interferes with expression of an aldose reductase gene (AKR1B1), so that AKR1B1 gene expression and/or aldose reductase protein levels are reduced compared to basal/wild-type levels.
  • aldose reductase gene does not require 100% abolition of expression and aldose reductase production; any level of reduced expression of aldose reductase may be beneficial to a subject.
  • the aldose reductase antisense oligonucleotide that reduces the expression of aldose reductase.
  • An ASO is a single-stranded deoxyribonucleotide, which is complementary to an mRNA target sequence.
  • the aldose reductase antisense oligonucleotide targets an exonic or intronic sequence of the aldose reductase gene.
  • Exemplary agents satisfying these criteria are provided in Table 2. Additional exemplary ASO sequences and filter criteria are shown in FIGS. 16-18 .
  • the nucleotide backbone of ASO sequences are modified to a chimeric or gapmer design to reduce gene expression when compared to basal/wild-type levels.
  • a gapmer design requires a designation of 3-5 nucleotides on each end of the antisense oligonucleotide sequence to harbor modifications in the ribose sugar moiety resistant to RNase H recognition and other nucleases, while all other nucleotides contain an RNase H compatible modification.
  • RNase H is responsible for cleaving RNA-DNA duplexes such as those formed between aberrant mRNA transcripts and synthetically designed DNA antisense oligonucleotides.
  • the modification to the ASO sequences includes, but is not limited to Phosphorothioate (PS)—RNase H recognizable, phosphorodiamidate morpholino (PMO)—RNase H resistant, 2′-O-methyl—RNase H resistant, 2′-O-methoxyethyl (MOE)—RNase H resistant, locked Nucleic Acid (LNA)—RNase H resistant, ethylene-bridged nucleic acid (ENA)—RNase H resistant, or (S)-constrained ethyl (cEt)—RNase H resistant.
  • Phosphorothioate PS
  • PMO phosphorodiamidate morpholino
  • MOE 2′-O-methoxyethyl
  • LNA locked Nucleic Acid
  • ENA ethylene-bridged nucleic acid
  • cEt relaxed ethyl
  • RNA interference RNA interference
  • RNAi RNA interference
  • Suitable agents include, e.g., siRNA, miRNA, and shRNA.
  • a shRNA/Hairpin Vector is an artificial RNA molecule (nucleotide) with a tight hairpin turn that can be used to silence target gene expression via RNAi.
  • shRNA is an advantageous mediator of RNAi in that it has a relatively low rate of degradation and turnover, but it often requires use of an expression vector.
  • the disclosure includes the production and administration of an AAV vector expressing one or more shRNAs targeting SORD.
  • shRNAs are regulated by the use of various promoters.
  • polymerase II promoters such as U6 and H1, and polymerase III promoters are used.
  • U6 shRNAs are used.
  • RNAi also may be used to downregulate (i.e., block) expression of aldose reductase (e.g., AKR1B1); as such, the disclosure contemplates sue of siRNA, miRNA, and shRNA which targets aldose reductase intronic or extronic sequences to block the expression of aldose reductase.
  • shRNA sequences are usually transcribed inside the cell nucleus from a vector containing a Pol III promoter such as U6.
  • the endogenous U6 promoter normally controls expression of the U6 RNA, a small RNA involved in splicing, and has been well-characterized (Kunkel et al., Nature. 322(6074):73-7 (1986); Kunkel et al., Genes Dev. 2(2):196-204 (1988); Paule et al., Nucleic Acids Res. 28(6):1283-98 (2000)).
  • the disclosure includes both murine and human U6 or H1 promoters.
  • the shRNA containing the sense and antisense sequences from a target gene connected by a loop is transported from the nucleus into the cytoplasm where Dicer processes it into siRNAs.
  • an agent that corrects the mutation in the SORD gene is employed.
  • An agent that corrects the mutation in SORD gene refers to an agent capable of modifying the SORD coding sequence or a regulatory element and/or non-coding region associated with the SORD gene to achieve a desired change in the sequence.
  • genome editing may be used to replace part or all of the SORD gene sequence or alter SORD protein expression levels.
  • the agent may comprise components employed in genome-editing techniques, such as designer zinc fingers, transcription activator-like effectors nucleases (TALENs), or CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated) systems.
  • An exemplary agent for use in the method of the disclosure is, DNA encoding Cas9 molecules and/or gRNA molecules.
  • Cas9 and gRNA can be present in a single expression vector or separate expression vectors.
  • Adenoviral delivery of the CRISPR/Cas9 system is described in Holkers et al., Nature Methods (2014), 11(10):1051-1057 which is incorporated by reference in its entirety.
  • CRISPR/Cas9 multiplexing may be used to target multiple genomic loci wherein two or more guide RNAs are expressed as described in CRISPR 101: A Desktop Resource (1 st Edition), Addgene , January 2016 which is incorporated by reference in its entirety.
  • treating refers to reducing or ameliorating inherited neuropathy and/or associated disorders and/or symptoms associated therewith. These terms include reducing or delaying the frequency of occurrence or recurrence of the neuropathy or symptoms associated therewith (i.e., lengthening the period of remission in a patient who had suffered from the disorder), as well as reducing the severity of the disorder or any symptoms associated therewith. It is appreciated that, although not precluded, “treating” or “treatment” of a disorder or condition does not require that the disorder, condition, or symptoms associated therewith be completely eliminated.
  • a dose of an active agent e.g., an aldose reductase inhibitor, an aldose reductase antisense oligonucleotide, a polynucleotide that encodes a SORD peptide, a SORD peptide, an agent that blocks expression of a mutant SORD gene, or an agent that corrects the mutation in SORD gene
  • an active agent e.g., an aldose reductase inhibitor, an aldose reductase antisense oligonucleotide, a polynucleotide that encodes a SORD peptide, a SORD peptide, an agent that blocks expression of a mutant SORD gene, or an agent that corrects the mutation in SORD gene
  • route of administration e.g., local vs. systemic
  • patient characteristics e.g., gender, weight, health, side effects
  • the nature and extent of the inherited neuropathy or associated disorder e.g., the particular active agent or combination of active
  • the active agents described herein are provided in a composition (e.g., a pharmaceutically-acceptable composition) which may contain formulation components suitable for administration to a subject, as well as additional therapeutic agents. Suitable methods of administering a physiologically-acceptable composition, such as a pharmaceutical composition comprising an agent described herein, are well known in the art.
  • a physiologically-acceptable composition such as a pharmaceutical composition comprising an agent described herein, are well known in the art.
  • more than one route can be used to administer one or more of the agents disclosed herein.
  • a particular route can provide a more immediate and more effective reaction than another route.
  • compositions orally through injection or infusion by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means; by controlled, delayed, sustained or otherwise modified release systems; by implantation devices; using nanoparticles; or as a conjugate.
  • the two or more active agents described herein may be administered as part of a therapeutic regimen.
  • one or more of the active agents may be administered with other therapeutics as part of a therapeutic regimen.
  • the active agent(s) may be administered as a monotherapy or as a combination therapy with other treatments administered simultaneously or metronomically.
  • the term “simultaneous” or “simultaneously” refers to administration of two agents within six hours or less (e.g., within three hours or within one hour each other).
  • multiple active (or therapeutic) agents may be administered the same composition or in separate compositions provided within a short period of time (e.g., within 30 minutes).
  • micronomically means the administration of different agents at different times and at a frequency relative to repeat administration. Active agents need not be administered at the same time or by the same route; preferably, in various embodiments, there is an overlap in the time period during which different active agents are exerting their therapeutic effect. Additional aspects and details of the disclosure will be apparent from the following examples, which are intended to be illustrative rather than limiting.
  • PCR Polymerase chain reaction
  • Fibroblasts were obtained from patients and cultured in Dulbecco's Modified Eagle Medium (ThermoFisher) supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin (Gibco). Cells were maintained in 5% CO 2 at 37° C. in a humidified incubator. Asynchronous cell cultures were grown to approximately 80% confluency and treated with epalrestat (10004), ranirestat (10 ⁇ M) or DMSO for 72 hours. Media containing the drugs or DMSO were changed every 24 hours.
  • Dulbecco's Modified Eagle Medium ThermoFisher
  • FBS fetal bovine serum
  • Gibco penicillin and streptomycin
  • Fibroblasts were lysed in RIPA buffer (ThermoFisher) containing protease inhibitor (Roche) and sonicated for 5 minutes with the Bioruptor sonication device (Diagenode). Cell lysates were centrifuged at 13,000 ⁇ g for 10 minutes at 4° C., and the supernatant was collected for protein quantification (Pierce BCA Protein Assay Kit). 30 ⁇ g of protein sample was mixed with Bolt LDS Sample Buffer and Sample Reducing Agent (ThermoFisher) and heated at 90° C. for 5 min. Samples were loaded on Bolt 4-12% Bis-Tris Plus mini-gel followed by transfer into a nitrocellulose membrane (Bio-Rad).
  • Membrane was blocked with 5% non-fat milk and incubated with anti-SORD (ab189248, Abcam) antibody for 2 hours, washed with TB S containing 0.01% Tween 20 (Bio-Rad) and incubated with a secondary anti-rabbit antibody (Cell Signaling). Membrane was subsequently incubated with GAPDH primary antibody (Santa Cruz) and secondary anti-mouse antibody (Cell Signaling). Chemoluminescence detection was performed with the SuperSignal West Pico PLUS Chemiluminescent Substrate and imaged with the FluorChem E (ProteinSimple).
  • Fibroblasts were collected and lysed as described in Western blot section in the absence of proteinase inhibitor. Sorbitol determination in human fibroblast lysates was performed in ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) (Waters Acquity UPLC & TQD mass spectrometer—Waters, Milford, Mass., USA). Fibroblasts were collected and lysed as described in Western blot section in the absence of proteinase inhibitor. Proteinase inhibitor contains high concentration mannitol, which is a sorbitol enantiomer, and can interfere with UPLC-MS/MS sorbitol determination.
  • UPLC-MS/MS ultra-performance liquid chromatography-tandem mass spectrometry
  • Lysate samples underwent protein precipitation with Acetonitrile (1:5), ten-time dilution with Acetonitrile-water (50/50) and clean up on Oasis HLB cartridges (10 mg/1 ml), before injection in UPLC (3 ⁇ L).
  • UPLC conditions column, BEH Amide 1.7 ⁇ m (2.1 ⁇ 100 mm) at 88° C., eluent A, Acetonitrile 90%-water 5%-Isopropanol 5%, eluent B, Acetonitrile 80%-water 20%, gradient elution 0 min., 100% A, 3.6 min. 100% B, flow rate, 0.45 ml/min. The retention time of sorbitol was 2.7 min.
  • MS/MS conditions interface, Electrospray interface in negative ion mode, Multiple Reaction Monitoring acquisition, m/z 180.9 ⁇ 88.9 (CV 24, CE 15).
  • Epalrestat or ranirestat was dissolved in dimethyl sulfoxide (DMSO) to achieve a stock concentration of 10 mg/ml, and then mixed into 10 ml fly food at a final concentration of 80 ⁇ g/ml. Equal amount of DMSO was mixed into the fly food as control. The vials were dried at room temperature for 12 h before feeding.
  • DMSO dimethyl sulfoxide
  • lifespan assay 100 newly enclosed female flies of each group were collected and placed in vials of 20 individuals. Flies were transferred into new vials every 2 days and the number of dead flies was counted. Survival data was plotted using Kaplan-Meier plot and compared between groups using log-rank test.
  • negative geotaxis behavior assay 10 age-matched female flies were placed in a vial marked with a black line drawn horizontally 8 cm above the bottom. Flies were given 60 min to fully recover from CO 2 anesthesia, and were gently tapped onto the bottom and given 10 s to climb. Flies that crossed the 8 cm line were counted.
  • this assay was repeated 10 times, and 10 independent vials of each group (a total 100 flies per group) were tested. To minimize observer-expectancy bias, this assay was performed with the examiner masked to the group assignment.
  • Brain dissection and staining were carried out as previously described (Brazill et al., J Vis Exp. 2018; (138)). Briefly, fly brains were dissected in phosphate-buffered saline (PBS, pH 7.4), fixed in 4% formaldehyde for 10 min, and washed in PBTX (PBS containing 0.4% v/v Triton X-100) for 3 times (15 mins each). Brains were then incubated with primary mouse anti-BRP antibody (nc82, Developmental Studies Hybridoma Bank) at 1:250 dilution in 0.4% PBTX with 5% normal goat serum at 4° C. overnight with gentle shaking.
  • PBS phosphate-buffered saline
  • PBTX PBS containing 0.4% v/v Triton X-100
  • CMT Charcot-Marie-Tooth disease
  • CMT1 demyelinating
  • CMT2 axonal
  • dHMN Distal hereditary motor neuropathy
  • SORD2P has a non-functional highly homologous paralogue, the pseudogene SORD2P, which is thought to arise from the duplication of SORD within a 0.5 Mb region on chromosome 15 (Carr et al. 2016) ( FIG. 1E ).
  • primers were designed that took advantage of nucleotide sequence differences and distinct retrotransposon insertions in both genic regions ( FIG. 5 ).
  • the c.757delG; p.(Ala253GlnfsTer27) mutation in exon 7 of SORD is fixated in the pseudogene SORP2P in over 95% of control chromosomes, along with numerous additional exonic indel mutations, which prevent effective translation of SOPR2P (1000 Genomes Project Consortium et al. 2015; Lek et al. 2016). Because of the high similarity of the regions, a nested PCR approach was necessary to obtain specific amplification of exon 7 of SORD and distinguish it from the homologous region in SORD2P. The presence of the variants detected by WES was confirmed by Sanger sequencing in all cases and segregation data in immediate relative carriers was provided. ( FIG. 1F and FIG. 5 ).
  • a third independent set of 297 recessive or sporadic CMT2/dHMN patients was screened by targeted Sanger sequencing of exon 7 of SORD, which was extended to the other coding exons if one c.757delG; p.(Ala253GlnfsTer27) was identified, and revealed 20 additional cases (7%) from 18 families with biallelic mutations in SORD: 16 cases with a homozygous c.757delG; p.(Ala253GlnfsTer27) mutation and four cases with c.757delG; p.(Ala253GlnfsTer27) in compound heterozygous state with a second likely pathogenic variant.
  • the allelic carrier frequency of the c.757delG; p.(Ala253GlnfsTer27) variant in the normal population is 0.003% based on an allelic count of 94 out of 30,872 in gnomAD genomes (Lek et al. 2016).
  • GENESIS uses the FreeBayes software for variant calling (Gonzalez et al.
  • Sorbitol dehydrogenase is a homotetrameric enzyme of 38-kDa subunits, which is widely distributed in mammalian tissues (Johansson et al. 2001; Hellgren et al. 2007; Lindstad, Teigen, and Skjeldal 2013). It represents the second enzyme of the two-step polyol pathway, in which glucose is converted to sorbitol, a relatively non-metabolizable sugar, by the enzyme aldose reductase (AR). Sorbitol is then oxidized to fructose by SORD ( FIG. 2A ).
  • SORD protein was absent in all patients and the wild-type levels were reduced in unaffected carriers compared to controls ( FIG. 2B ). Accordingly, intracellular sorbitol concentrations were over 10 times higher in patients' fibroblasts compared to controls, in keeping with a loss of SORD enzymatic activity ( FIG. 2C ). Fasting sorbitol levels in serum from ten patients carrying the homozygous p.Ala253GlnfsTer27 mutation and ten unrelated controls and found it was over 100 times higher (14.82 ⁇ 0.780 vs 0.046 ⁇ 0.004 mg/L, p ⁇ 0.0001) was determined, confirming the lack of SORD enzymatic activity in patients ( FIG. 13 ). This study also demonstrates that sorbitol is a useful marker for detecting or characterizing inherited neuropathy associated with SORD mutation in a mammalian subject.
  • Drosophila melanogaster models of SORD deficiency were established.
  • Drosophila has two functional SORD genes (Sodh1 and Sodh2) that share 90% residue identity (Luque et al. 1998).
  • Sodh1 NP 001287203.1
  • Sodh2 NCBI Reference Sequence: NP 524311.1 encoded proteins share 75% and 73% identity with human SORD protein (NCBI Reference Sequence: NP 003095.2 (SEQ ID NO: 46)), respectively.
  • Sodh2 MB01265 A mutant allele of Sodh2 was obtained where the gene is disrupted by a transposon Minos mediated integration cassette (MiMIC) insertion (Sodh2 MB01265 ) (Bellen et al. 2011). Homozygous Sodh2 (Sodh2 MB01265/MB01265 ) mutants are viable with normal life span.
  • MiMIC transposon Minos mediated integration cassette
  • Sodh2 MB01265/MB01265 Homozygous Sodh2 (Sodh2 MB01265/MB01265 ) mutants are viable with normal life span.
  • the Drosophila visual system was used to take advantage of the highly organized parallel axons of the compound eye that allow in vivo detection of subtle neuronal and synaptic pathological changes (Bausenwein, Dittrich, and Fischbach 1992).
  • Axons of the outer photoreceptor axons traverse the lamina cortex and make synaptic connections with lamina monopolar neurons in the lamina layer ( FIG. 3A ).
  • the organized lamina cartridges of photoreceptor synapses can be visualized in the xy- and xz-planes, respectively ( FIG. 3B ).
  • a loss of photoreceptor terminals in the lamina layer of Sodh2 MB01265/MB01265 mutants was observed at 2 days after eclosion (DAE) ( FIG. 3C ).
  • sorbitol levels were measured in fly heads at 10 DAE and observed a significant increase in the Sodh2 MB01265/MB01265 model ( FIG. 4B ), consistent with the observation in patient fibroblasts.
  • Drosophila models of SORD deficiency were successfully established that recapitulate typical pathological phenotypes in human patients, including (1) a normal lifespan, (2) progressive and age-dependent synaptic degeneration and locomotor deficiency, and (3) increased sorbitol levels.
  • SORD represents a novel recessive gene causing axonal/intermediate, motor predominant CMT.
  • Genetic data from the cohort as well as from control databases suggest that the predominant pathogenic variant in SORD, c.757delG; p.(Ala253GlnfsTer27), with a carrier frequency in of ⁇ 3/1,000 individuals in the population, may represent one of the most common specific alleles causing a recessive Mendelian disease. Indeed, with a frequency in undiagnosed CMT2 and dHMN cases of up to ⁇ 10%, it will likely account for a significant portion of the diagnostic gap in inherited axonal neuropathies.

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