NAP for sex-specific treatment of diseases

Abstract

The present invention provides methods for gender-specific treatment and dose titration of diseases associated with abnormal functionality of Activity-Dependent Neuroprotective Protein (ADNP) and / or cytoskeleton, such as Progressive Supranuclear Palsy (PSP), schizophrenia, amnestic Mild Cognitive Impairment (aMCI), Alzheimer's disease, and autism. Treatments, e.g., doses and / or regimens, in these diseases vary by gender and must be adapted to achieve the desired effect. In particular, the use of davunetide in the treatment of women suffering from PSP or men suffering from schizophrenia or aMCI is provided.

Description

[Technical field]

[0001] The present invention relates to the gender-specific treatment of diseases associated with abnormal functionality of Activity-Dependent Neuroprotective Protein (ADNP) or diseases closely related to microtubule (cytoskeleton) function, such as the treatment of women suffering from Progressive Supranuclear Palsy, men suffering from schizophrenia or amnesic mild cognitive impairment. [Background technology]

[0002] NAP (NAPVSIPQ single amino acid letter code, also known as davunetide, AL-108, CP201, and sometimes referred to as NAP peptide) is the minimal neuroprotective peptide moiety of the action-dependent neuroprotective protein (ADNP). NAP and pipeline products protect neurons by associating with microtubule end-associated proteins (EB1 / EB3) via an SxIP motif (NAPVSIPQ), thus enhancing microtubule dynamics and tau-microtubule interactions and protecting synapses. NAP further enhances ADNP-EB1 / EB3 interactions and protects against ADNP deficiency (see Hacohen-Kleiman et al., The Journal of clinical investigation 2018, 128(11):4956-4969). Recently, a homology 3 (SH3) domain-ligand association site in NAP (NAPVISP) has been shown to involve actin-tau interactions and to be involved in the control of signaling pathways that regulate the cytoskeleton (Ivashko-Pachima et al., Mol Psychiatry. 2022, 27(8):3316-3327).

[0003] Progressive Supranuclear Palsy (PSP) is a rare and fatal neurodegenerative movement disorder for which no disease modifying therapy (DMT) is currently available. Symptoms include changes in speech, balance, gait, swallowing, vision, cognition, autonomic function, and Parkinsonian symptoms such as tremor, rigidity, and slowness. PSP is a rapidly progressive neurodegenerative disease and tauopathy caused by abnormal folding of the protein tau in brain cells.

[0004] The most common tauopathy is Alzheimer's disease, but other less common tauopathies exist as well. Tauopathies can also be found in other brain diseases, including, but not limited to, Amyotrophic Lateral Sclerosis (ALS) and Autism. All of these diseases currently lack disease-modifying therapeutic agents.

[0005] More comprehensively, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA) are brain diseases that can cause changes in speech, balance, walking, swallowing, vision, cognition, and autonomic function. These diseases can also include symptoms similar to Parkinson's disease, including tremors, rigidity, and slowness. This is why people are initially diagnosed with Parkinson's disease, and then hear PSP, CBD, and MSA referred to as "atypical parkinsonism" syndromes. They are neurodegenerative, meaning that symptoms can change and worsen over time.

[0006] PSP, CBD, and MSA are considered rare, especially when compared with more common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, however, only about 25% of people with PSP, CBD, and MSA are correctly diagnosed.

[0007] Davunetide (NAP) treatment showed enhanced cognitive scores in amnestic mild cognitive (aMCI) (Morimoto et al., Dementia and geriatric cognitive disorders 2013, 35(5-6):325-336) and protection of daily living activities in schizophrenia patients (Javitt et al., Schizophrenia research 2012, 136(1-3):25-31; Gozes I. Frontiers in neurology 2020, 11:608444). The choice of aMCI as a therapeutic target for davunetide is obvious because it protects against tauopathy and cell death, aMCI being the precursor of the major tauopathy, Alzheimer's disease. Selection for schizophrenia is similarly relevant as davunetide enhances the autophagy process, which is defective in schizophrenia, by enhancing microtubule dynamics. Importantly, ADNP regulates the autophagy process, interacting with autophagy regulatory proteins, e.g., microtubule-associated protein 1 light chain 3 (LC3), regulating Beclin 1 expression, and NAP (davunetide) enhances / replaces the defective ADNP defect and provides neuroprotection (Sragovich S, Merenlender-Wagner A, Gozes I. Bioessays. 2017, 39(11)).

[0008] Considering that tauopathy is the primary outcome of ADNP deficiency / pathological mutations in mice and humans (Grigg et al., Translational psychiatry 2020, 10(1):228), NAP (davunetide) has shown protection against tauopathy in multiple preclinical models, as well as increased cognitive scores in the aMCI study cited above, but clinical studies in pure tauopathy have been conducted in progressive supranuclear palsy (PSP) as an ideal target for davunetide protection. However, this study, while showing safety, did not meet its endpoints (see Boxer et al., The Lancet Neurology 2014, 13(7):676-685).

[0009] In trying to understand the results, one explanation suggests a dose above the bell-shaped dose response identified in preclinical studies (Bassan et al., Journal of neurochemistry 1999, 72(3):1283-1293; Leker et al., Stroke 2002, 33(4):1085-1092), which was further suggested in clinical trials. Thus, in schizophrenia, a daily dose of 5 mg was significantly more effective than placebo, but a higher dose of 15 mg twice daily was not significantly different from the 5 mg daily dose and placebo, possibly due to underpowering and high variability, suggesting plateauing towards a bell-shaped response (Javitt et al.). In aMCI, there was a dose-dependence (at the doses above), suggesting disease specificity (Morimoto et al.). However, the dose used in PSP (30 mg twice daily) was twice as high as the highest aMCI and schizophrenia dose likely to achieve a bell-shaped response.

[0010] Another study to explain the results looked at tau in more detail. Indeed, understanding the regulation of tau (MAPT (Microtubule Associated Protein Tau) mRNA splicing is important for the purpose of solving the pathogenesis of PSP as well as other tauopathies. Tauopathies can be classified by the presence of tau aggregates containing 3 (3R) and / or 4 (4R) microtubule binding domain repeats (determined by the inclusion / exclusion of MAPT exon 10) and by the inclusion / exclusion of exon 2 and exon 3, which translate into two N-terminal tau domains, with the accumulation of the 1N4R isoform in PSP and the 0N isoform in Alzheimer's disease temporal cortex. Importantly, NAP (davunetide) / ADNP enhances tau microtubule association (Ivashko-Pachima et al., Molecular psychiatry 2017, 22(9):1335-1344), and ADNP in turn may directly interact with the splicing machinery to suppress inclusion of exon 10. Furthermore, davunetide testing in pure 4-repeat tau (PSP), a potentially ideal population target for davunetide protection, was deemed negative (Boxer et al.), but retrospectively, some of the negative results were attributed to preferential enhancement of NAPs of dynamic 3-repeat tau (containing three microtubule interaction sites) over 4-repeat tau-microtubule interactions (Ivashko-Pachima et al., PLoS One 2019, 4(3)):e0213666).

[0011] Finally, in an attempt to understand what drives PSP tauopathy, elucidating studies have identified genetic mutations and increased filamin A in PSP brains. Accordingly, increased filamin A levels enhanced tau phosphorylation and tau insolubility through interacting actin filaments. Furthermore, reduction of filamin A corrected abnormal tau levels in cultured cells from PSP cases, and transgenic mice carrying human filamin A recapitulated tau pathology in neurons (Tsujikawa et al., Science advances 2022, 8(21):eabm5029). In this regard, the inventors have shown that ADNP contains an actin-binding domain and NAP modifies actin-associated protein interactions (Ivashko-Pachima et al., Molecular psychiatry 2022, J.27(8):3316-3327).

[0012] The efficacy of NAP was tested in patients suffering from schizophrenia, another neurological disorder associated with abnormal ADNP (Javitt et al., Schizophrenia research 2012, 136(1-3):25-31). Subjects treated with a daily dose of 5 mg had significantly higher post-dose UCSD Performance-based Skills Assessment (UPSA) scores than the placebo group. Patients treated with a higher dose of 30 mg (15 mg twice daily) had scores that were not significantly different from the 5 mg daily dose and from placebo.

[0013] PSP and other neurodegenerative diseases still have no cure and there is an urgent need to provide such. Similarly, cognitive impairment in schizophrenia has not been adequately addressed, and developmental disorders including but not limited to autism spectrum disorder and Alzheimer's disease are also unmet medical needs. Summary of the Invention

[0014] The present invention is based on the unexpected observation that men and women suffering from PSP respond differently to treatment with NAP peptide (also called davunetide). In the examples, the inventors show that diseased men did not benefit from treatment with NAP, but significant improvement was observed in treated women. The inventors found that NAP peptide reduced the increase in ventricle size caused by neurodegeneration in women. This was not observed in men. The finding that NAP protein can be used to treat PSP contradicts previous statements, for example, by Boxer et al. (The Lancet Neurology 2014, 13(7):676-685), which clearly state that davunetide is not an effective treatment for PSP. Furthermore, based on the inventors' understanding of the mechanism of tauopathy associated with abnormal ADNP protein, particularly the development of Alzheimer's disease, we found that gender-specific treatment is effective in these diseases and conditions. Furthermore, since the neurodegenerative side effects of some biological anti-amyloid beta therapies, such as aducanumab, are expressed in an increase in ventricles, the inventors have found that NAP may be beneficial in reducing said side effects, especially in a sex-specific manner. Furthermore, the inventors have shown that treating men suffering from schizophrenia with 30 mg / day of NAP significantly improved their symptoms. This was not observed in women. A similar observation was made for men suffering from amnesic mild cognitive impairment, but treatment of men with 30 mg / day of NAP resulted in significant improvement of their symptoms. For women, a much higher dose appears to be required. Thus, according to one aspect, the present invention provides a pharmaceutical composition for use in treating or suppressing the development of a disease or disorder associated with abnormal functioning of action-dependent neuroprotective protein (ADNP) in a sex-specific manner in a subject, comprising a peptide (NAPVSIPQ:NAP peptide) comprising the amino acid sequence of SEQ ID NO: 1 and a pharma- ceutical acceptable carrier. According to some embodiments, the disease or disorder is selected from a neurodegenerative disease, a neurodevelopmental or psychiatric disease, and a tauopathy.In some embodiments, the disease is a tauopathy. In some embodiments, the disease or disorder is selected from progressive supranuclear palsy (PSP), schizophrenia, Alzheimer's disease, amnesic mild cognitive impairment (aMCI), ADNP syndrome, autism, and muscle disease.

[0015] According to some embodiments, the disease is progressive supranuclear palsy (PSP) and the use comprises treating or inhibiting the onset of PSP in a female subject. In some embodiments, treating or preventing the onset of PSP comprises preventing or inhibiting an increase in ventricular size. According to some embodiments, the use comprises administering 1-80 mg / day of NAP peptide. According to some embodiments, the use comprises administering 40-80 mg / day of NAP peptide.

[0016] According to some embodiments, the disease is progressive supranuclear palsy (PSP) and the use comprises treating PSP in a male subject comprising administering to the subject 1 to 50 mg / day of NAP.

[0017] According to some embodiments, the disease is schizophrenia and the use comprises treating schizophrenia in a male subject, the use comprises administering to the male subject 10-80 mg / day of the NAP peptide. According to some embodiments, the use comprises administering to the male subject 20-80 mg / day of the NAP peptide.

[0018] According to some embodiments, the disease is schizophrenia and the use comprises treating schizophrenia in a female subject, the use comprises administering to the subject 1-4 mg / day of a NAP peptide.

[0019] According to some embodiments, the disease is amnesic mild cognitive impairment (aMCI) and the use comprises treating amnesic aMCI in a male subject, the use comprises administering to the subject 10-80 mg / day or 25-80 mg / day of NAP peptide.

[0020] According to some embodiments, the disease is amnesic mild cognitive impairment (aMCI) and the use comprises treating amnesic aMCI in a female subject, the use comprises administering to the subject 35-80 mg / day of NAP peptide.

[0021] According to some embodiments, the use comprises gender-specific treatment or prevention of Alzheimer's disease. According to some embodiments, the use comprises treatment or prevention in the prodromal stage of the disease. According to some embodiments, Alzheimer's disease is characterized by the presence in a biological sample of at least one of the following: (i) abnormal P53 protein, (ii) P-tau217, (iii) P-tau231, and (iii) P-tau181, and (iv) altered ADNP expression.

[0022] According to some embodiments, the use comprises treating a female subject and comprises administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of NAP.

[0023] According to some embodiments, the use comprises treating a male subject and comprises administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of NAP.

[0024] According to another aspect, the present invention provides a method for treating or inhibiting the onset of a disease or disorder associated with abnormal function of action-dependent neuroprotective protein (ADNP) in a subject, comprising administering to the subject a peptide comprising the amino acid sequence of SEQ ID NO:1 (NAPVSIPQ, NAP peptide) in a sex-specific manner / manner.

[0025] According to some embodiments, the present invention provides a method of treating or inhibiting the development of PSP in a female subject, comprising administering to the female subject a peptide comprising the amino acid sequence of SEQ ID NO: 1. According to some embodiments, the method comprises administering 40-80 mg / day of the NAP peptide.

[0026] According to some embodiments, the present invention provides a method for treating or inhibiting the development of PSP in a male subject, comprising administering to the subject 1-50 mg / day of NAP.

[0027] According to some embodiments, the present invention provides a method for treating schizophrenia in a male subject, comprising administering to the male subject 10-80 mg / day of a NAP peptide. According to some embodiments, the method comprises administering to the male subject 20-80 mg / day of a NAP peptide.

[0028] According to some embodiments, the present invention provides a method for treating schizophrenia in a female subject, the method comprising administering to the subject 1-4 mg / day of a NAP peptide.

[0029] According to some embodiments, the present invention provides a method for treating amnesic mild cognitive impairment (aMCI), comprising treating aMCI in a male subject, wherein using comprises administering to the subject 10-80 mg / day or 25-80 mg / day of NAP peptide.

[0030] According to some embodiments, the present invention provides a method for treating amnesic aMCI in a female subject, the method comprising administering to the subject 35-80 mg / day of NAP peptide.

[0031] According to some embodiments, the present invention provides a method for treating or preventing Alzheimer's disease in a subject in need thereof in a sex-specific manner. According to some embodiments, the treatment or prevention is in a prodromal stage of the disease. According to some embodiments, the Alzheimer's disease is characterized by the presence in a biological sample of at least one of the following: (i) abnormal P53 protein, (ii) P-tau217, (iii) P-tau231, and (iii) P-tau181, and (iv) altered ADNP expression. According to some embodiments, the method includes treating a female subject and includes administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of NAP. According to some embodiments, the method includes treating a male subject and includes administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of NAP.

[0032] According to another aspect, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ and a pharma- ceutical acceptable carrier for use in ameliorating and / or preventing side effects of an anti-amyloid beta therapy, wherein the therapy comprises an anti-amyloid beta antibody. According to some embodiments, the composition is administered in a sex-specific manner.

[0033] According to some embodiments, the composition is administered to a female subject at a dose of, for example, 1-70 mg / day or 50-70 mg / day of NAP.

[0034] According to some embodiments, the composition is administered to a male subject at a dose of, for example, 1-70 mg / day, 1-50 mg / day, or 50-70 mg / day of NAP.

[0035] According to some embodiments, the anti-amyloid beta therapy comprises aducanumab or lecanemab.

[0036] According to any one of the above aspects and embodiments, the NAP peptide or a pharmaceutical composition comprising the NAP peptide is administered intranasally.

[0037] According to any one of the above aspects and embodiments, the gender-specific treatment comprises inhibiting neurodegeneration in the subject. [Brief description of the drawings]

[0038] [Figure 1A] Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (Figure 1A - weight), and for those at baseline, the studied populations differed in weight, height, and ventricular volume, with significantly higher values ​​in males. [Figure 1B] Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (FIG. 1B-height), and for those at baseline, the studied populations differed in weight, height, and ventricular volume, with significantly higher values ​​in males. [Figure 1C] Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (FIG. 1C-age), and for those at baseline, the studied populations differed in weight, height, and ventricular volume, with significantly higher values ​​in males. [Figure 1D] Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (FIG. 1D - ventricular volumes), with those at baseline the studied populations differing in weight, height, and ventricular volumes, with significantly higher values ​​in males. [Figure 1E]Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (Figure 1E - SEADL (Schwab and England Activities of Daily Living Scale)), where at baseline the studied populations differed in weight, height, and ventricular volume, with significantly higher values ​​in men. [Figure 1F] Baseline demographics are shown for PSP subjects treated with placebo or NAP and stratified by sex (Figure 1F-PSPRS), where at baseline the studied populations differed in weight, height, and ventricular volume, with significantly higher values ​​in males. [Diagram 2] A linear regression is shown correlating the baseline percent change in ventricular volume at week 52 with age, as measured by MRI in men and women treated with davunetide and placebo. [Diagram 3] Linear regression is shown correlating ventricular volume at week 52 with baseline ventricular volume (mm) measured by MRI in men and women treated with davunetide and placebo separately. [Figure 4A] 1 shows the reduction in total tau in cerebrospinal fluid (CSF) of female patients treated with davunetide compared to placebo. [Figure 4B] Figure 1 shows a reduction in phosphorylated tau in cerebrospinal fluid (CSF) of female patients treated with davunetide compared to placebo. [Diagram 5]Correlation plot r values ​​using percent change compared to baseline in davunetide versus placebo outcomes at week 52, including the study's primary endpoints PSPRS and SEADL, secondary endpoints ventricular volume change, and age. Significance is indicated by *P<0.05, **P<0.01, and ***P<0.001. "." indicates #P<0.1 and >0.05. [Figure 6A] Linear regression plots, (FIG. 6A) PSPRS, (FIG. 6B) PSPRS limb motor domain, (FIG. 6C) SEADL, (FIG. 6D) tables comparing changes in male and female placebo groups over the 52-week study show statistically significant accelerated deterioration in men treated with davunetide. * indicates significance, #P<0.1 and >0.05 compared to placebo as detailed in the figures. [Figure 6B] Linear regression plots, (FIG. 6A) PSPRS, (FIG. 6B) PSPRS limb motor domain, (FIG. 6C) SEADL, (FIG. 6D) tables comparing changes in male and female placebo groups over the 52-week study show statistically significant accelerated deterioration in men treated with davunetide. * indicates significance, #P<0.1 and >0.05 compared to placebo as detailed in the figures. [Figure 6C] Linear regression plots, (FIG. 6A) PSPRS, (FIG. 6B) PSPRS limb motor domain, (FIG. 6C) SEADL, (FIG. 6D) tables comparing changes in male and female placebo groups over the 52-week study show statistically significant accelerated deterioration in men treated with davunetide. * indicates significance, #P<0.1 and >0.05 compared to placebo as detailed in the figures. [Figure 6D] Linear regression plots, (FIG. 6A) PSPRS, (FIG. 6B) PSPRS limb motor domain, (FIG. 6C) SEADL, (FIG. 6D) tables comparing changes in male and female placebo groups over the 52-week study show statistically significant accelerated deterioration in men treated with davunetide. * indicates significance, #P<0.1 and >0.05 compared to placebo as detailed in the figures. [Figure 7A] Linear regression plots comparing change in davunetide versus placebo in women over the 52 week study are shown for (FIG. 7A) PSPRS, (FIG. 7B) behavioral domain of PSPRS, (FIG. 7C) bulbar domain of PSPRS, (FIG. 7D) SEADL. * indicates significance compared to placebo as detailed in the figure. [Figure 7B] Linear regression plots comparing change in davunetide versus placebo in women over the 52 week study are shown for (FIG. 7A) PSPRS, (FIG. 7B) behavioral domain of PSPRS, (FIG. 7C) bulbar domain of PSPRS, (FIG. 7D) SEADL. * indicates significance compared to placebo as detailed in the figure. [Figure 7C] Linear regression plots comparing change in davunetide versus placebo in women over the 52 week study are shown for (FIG. 7A) PSPRS, (FIG. 7B) behavioral domain of PSPRS, (FIG. 7C) bulbar domain of PSPRS, (FIG. 7D) SEADL. * indicates significance compared to placebo as detailed in the figure. [Figure 7D] Linear regression plots comparing change in davunetide versus placebo in women over the 52 week study are shown for (FIG. 7A) PSPRS, (FIG. 7B) behavioral domain of PSPRS, (FIG. 7C) bulbar domain of PSPRS, (FIG. 7D) SEADL. * indicates significance compared to placebo as detailed in the figure. [Figure 8A] The exploratory endpoint GDS (Geriatric depression scale) change from baseline to week 52 results for davunetide versus placebo in women (FIG. 8A) and men (FIG. 8B) are shown. [Figure 8B]The exploratory endpoint GDS (Geriatric depression scale) change from baseline to week 52 results for davunetide versus placebo in women (FIG. 8A) and men (FIG. 8B) are shown. [Figure 9A] FIG. 9 shows the effect of davunetide versus placebo on the change from baseline to week 16 in elderly patients with amnesic mild cognitive impairment (aMCI). The DMTS scale measured the change in the rate of correct recognition of objects after a 12-second delay (visual short-term memory and verbal working memory). Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over the 12-week study, with evaluations every 4 weeks, including a further evaluation 4 weeks after cessation of treatment. The change in DMTS scale from baseline was measured and is shown as follows: FIG. 9A-female, 5 mg / day; FIG. 9B-female, 15 mg / bid; FIG. 9C-male, 5 mg / day; and FIG. 9D-male, 15 mg / bid. **P<0.01, #P<0.1>0.5. [Figure 9B] FIG. 9 shows the effect of davunetide versus placebo on the change from baseline to week 16 in elderly patients with amnesic mild cognitive impairment (aMCI). The DMTS scale measured the change in the rate of correct recognition of objects after a 12-second delay (visual short-term memory and verbal working memory). Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over the 12-week study, with evaluations every 4 weeks, including a further evaluation 4 weeks after cessation of treatment. The change in DMTS scale from baseline was measured and is shown as follows: FIG. 9A-female, 5 mg / day; FIG. 9B-female, 15 mg / bid; FIG. 9C-male, 5 mg / day; and FIG. 9D-male, 15 mg / bid. **P<0.01, #P<0.1>0.5. [Figure 9C]FIG. 9 shows the effect of davunetide versus placebo on the change from baseline to week 16 in elderly patients with amnesic mild cognitive impairment (aMCI). The DMTS scale measured the change in the rate of correct recognition of objects after a 12-second delay (visual short-term memory and verbal working memory). Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over the 12-week study, with evaluations every 4 weeks, including a further evaluation 4 weeks after cessation of treatment. The change in DMTS scale from baseline was measured and is shown as follows: FIG. 9A-female, 5 mg / day; FIG. 9B-female, 15 mg / bid; FIG. 9C-male, 5 mg / day; and FIG. 9D-male, 15 mg / bid. **P<0.01, #P<0.1>0.5. [Figure 9D] FIG. 9 shows the effect of davunetide versus placebo on the change from baseline to week 16 in elderly patients with amnesic mild cognitive impairment (aMCI). The DMTS scale measured the change in the rate of correct recognition of objects after a 12-second delay (visual short-term memory and verbal working memory). Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over the 12-week study, with evaluations every 4 weeks, including a further evaluation 4 weeks after cessation of treatment. The change in DMTS scale from baseline was measured and is shown as follows: FIG. 9A-female, 5 mg / day; FIG. 9B-female, 15 mg / bid; FIG. 9C-male, 5 mg / day; and FIG. 9D-male, 15 mg / bid. **P<0.01, #P<0.1>0.5. [Figure 10A]FIG. 1 shows the effect of davunetide administration versus placebo administration on the change in UPSA scale from week 1 in patients diagnosed with schizophrenia. Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over a 6-week study or a 12-week study. The change in UPSA scale from week 1 was measured and shown as follows: FIG. 10A-female, 5 mg / day; FIG. 10B-female, 15 mg / bid; FIG. 10C-male, 5 mg / day; and FIG. 10D-male, 15 mg / bid. * indicates significance as detailed in the figure. # indicates trending. There is a significant difference of P=0.0276 between the female and male dose groups using 5 mg / day. All statistical comparisons included Student t-tests between the two groups. [Figure 10B] FIG. 1 shows the effect of davunetide administration versus placebo administration on the change in UPSA scale from week 1 in patients diagnosed with schizophrenia. Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over a 6-week study or a 12-week study. The change in UPSA scale from week 1 was measured and shown as follows: FIG. 10A-female, 5 mg / day; FIG. 10B-female, 15 mg / bid; FIG. 10C-male, 5 mg / day; and FIG. 10D-male, 15 mg / bid. * indicates significance as detailed in the figure. # indicates trending. There is a significant difference of P=0.0276 between the female and male dose groups using 5 mg / day. All statistical comparisons included Student t-tests between the two groups. [Figure 10C]FIG. 1 shows the effect of davunetide administration versus placebo administration on the change in UPSA scale from week 1 in patients diagnosed with schizophrenia. Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over a 6-week study or a 12-week study. The change in UPSA scale from week 1 was measured and shown as follows: FIG. 10A-female, 5 mg / day; FIG. 10B-female, 15 mg / bid; FIG. 10C-male, 5 mg / day; and FIG. 10D-male, 15 mg / bid. * indicates significance as detailed in the figure. # indicates trending. There is a significant difference of P=0.0276 between the female and male dose groups using 5 mg / day. All statistical comparisons included Student t-tests between the two groups. [Figure 10D] FIG. 1 shows the effect of davunetide administration versus placebo administration on the change in UPSA scale from week 1 in patients diagnosed with schizophrenia. Patients were treated with two doses of davunetide, 5 mg / day and 30 mg / day (15 mg / bid), over a 6-week study or a 12-week study. The change in UPSA scale from week 1 was measured and shown as follows: FIG. 10A-female, 5 mg / day; FIG. 10B-female, 15 mg / bid; FIG. 10C-male, 5 mg / day; and FIG. 10D-male, 15 mg / bid. * indicates significance as detailed in the figure. # indicates trending. There is a significant difference of P=0.0276 between the female and male dose groups using 5 mg / day. All statistical comparisons included Student t-tests between the two groups. [Figure 11] Inverse regulation of the gene in male and female mice with ADNP syndrome. Complete RNA sequencing of brain hippocampus samples shows inverse regulation in ADNP mutant HTR males and HTR females compared to wild type (WT) controls, but NAP corrects the intron retention event (abnormal alternative splicing) of Hace1 gene / mRNA in males treated with vehicle (saline) or NAP. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the patent specification, including definitions, shall control.

[0040] In one aspect, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAP peptide and a pharma- ceutical acceptable carrier for use in the gender-specific treatment, suppression of onset or prevention of a disease or disorder associated with abnormal functioning of action-dependent neuroprotective protein (ADNP) in a subject.

[0041] In some embodiments, the disease or disorder is selected from a neurodegenerative, neurodevelopmental or psychiatric disease, and a tauopathy. In some embodiments, the disease or disorder is a tauopathy.

[0042] The term "tauopathy" refers to a neurodegenerative disorder characterized by the deposition of abnormal tau protein in the brain. Tauopathy is a major consequence of ADNP deficiency or abnormal function.

[0043] The term abnormal functionality of the action-dependent neuroprotective protein (ADNP) encompasses any deviation from the normal function of the ADNP protein, typically caused by mutations resulting in non-functional dysfunction or truncation of the protein, for example due to the presence of a proteolytic site.

[0044] The term "Activity-Dependent Neuroprotective Protein" (ADNP) refers to a human protein factor (Bassan et al., Zamostiano et al., J Biol Chem. 2001, 276(1):708-14). This protein has neurotrophic / neuroprotective activity, for example, as measured by the in vitro cortical neuronal culture assay described by Gozes et al. (Proc. Natl. Acad. Sci. USA 93, 427-432, 1996, Bassan et al.) and discussed in Gozes. Book Chapter 13, in Neuroprotection in Alzheimer's Disease, 1st Edition-December 30, 2016, Gozes, Ed., Academic Press). ADNP regulates hundreds of genes. A non-limiting example is Hace1, shown in Example 5. Hace1 (HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1) associated with ataxia (Bellamy et al., PLoS One. 2022, 17(1):e0261845), Huntington's disease (Ehrnhoefer et al., Hum Mol Genet. 2018, 27(2):239-253. Mutations resulting in severe neurodevelopmental disorders (OMIM:616756) and further involvement in depression (Ciuculete et al., Clin Epigenetics. 2020, 12(1):99), and Alzheimer's disease (Ni et al., J Alzheimers Dis. 2018, 64(4):1149-1161).

[0045] The terms "NAP" and "NAP protein" are used interchangeably herein and refer to an 8-amino acid peptide consisting of amino acids NAPVSIPQ, as set forth in SEQ ID NO:1, and also known as davunetide (AL-108, also known as CP201).

[0046] Nevertheless, in its broadest definition, the term "NAP peptide" refers to a peptide that includes the amino acid sequence NAPVSIPQ, and any derivative or analog of a peptide that contains the amino acid sequence NAPVSIPQ or a related sequence and has the same biological activity, such as those defined in WO2008084483, WO2006099739, U.S. Patent Nos. 2012208763, and 20150141345, which are incorporated by reference in their entireties. According to some embodiments, the term NAP refers to one of the NAP's derivatives having an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 2-49, as well as the NAP alpha-aminoisobutyric acid family itself, or SKIP (Ivashko-Pachima et al., J Mol Neurosci. August 2021, 71(8):1515-1524), or Ac-SKIP (Ivashko-Pachima and Gozes (Front Cell Neurosci. October 1, 2019, 13:435. doi:10.3389 / fncel.2019.00435). According to some embodiments, the treatment method of the invention includes the use of other compounds that have an activity similar to that of NAP, i.e., substitutes for NAP, that modulate ADNP. Examples of such substitutes for NAP that modulate ADNP are described, for example, in Sragovich et al. (Translational Psychiatry volume 9, Article number:235 (2019)), SNV is SNV described in Eger et al. (Front Pharmacol. 2021 May 5, 12:638128. doi:10.3389 / fphar.2021.638128), or ketamine (Brown et al. 2015 April 2, 290:31-40).Additionally, NAP activity should also be considered in combination with other drugs, such as antipsychotics, including but not limited to risperidone or clozapine.

[0047] The term "treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, ameliorating, arresting, substantially inhibiting, slowing, or reversing the progression of a disease, condition, or disorder, substantially improving or alleviating clinical or aesthetic symptoms of a condition, substantially preventing the onset of clinical or aesthetic symptoms of a disease, condition, or disorder, and protecting against harmful or bothersome symptoms. Treating further refers to achieving one or more of the following: (a) reducing the severity of the disorder, (b) limiting the onset of symptoms characteristic of the disorder(s) being treated, (c) limiting the worsening of symptoms characteristic of the disorder(s) being treated, (d) limiting the recurrence of the disorder(s) in patients who previously had the disorder(s), and / or (e) limiting the recurrence of symptoms in patients who were previously asymptomatic for the disorder(s). In one embodiment, the term treating refers to inhibiting the progression of a disease or disorder. In other embodiments, the term refers to reversing or tapering off the progression of a disease or disorder. According to some embodiments, the term also refers to preventing a disease. As used herein, the term "preventing," when used in reference to a condition, refers to administration of a composition that reduces the frequency or delays the onset of symptoms of a medical condition in a subject compared to a subject not administered the composition.

[0048] As stated above, a major essence of the present invention is that the treatment of the diseases described herein is sex-specific. The term "sex-specific treatment" means that the treatment of males and females is different in terms of dosage, regimen, and outcome. Thus, a treatment may be effective for one gender and ineffective for the other, a dosage effective for one gender may be ineffective or even harmful for the other gender, etc. The terms "sex-specific" and "gender-specific" may be used interchangeably. The term "sex" refers to the biological sex of a subject as defined by genetics as is well known in the art. The terms "male", "males", "man", and "men" are used interchangeably herein. The terms "female", "femles", "woman", and "women" are used interchangeably herein.

[0049] The term "pharmaceutical composition" as used herein refers to a composition comprising at least one active agent disclosed herein, optionally formulated with one or more pharma- ceutically acceptable carriers. The formulation of the pharmaceutical composition may be adjusted depending on the application. In particular, the pharmaceutical composition may be formulated using methods well known in the art to provide immediate, continuous, or delayed release of the active ingredient after administration to a mammal. For example, the formulation may be any one of the following formulations selected from plasters, granules, lotions, liniments, limonases, perfumes, powders, syrups, eye ointments, liquids and solutions, aerosols, extracts, elixirs, ointments, liquid extracts, emulsions, suspensions, decoctions, infusions, eye drops, tablets, suppositories, injections, spirits, capsules, creams, troches, tinctures, pastes, pills, and soft or hard gelatin capsules.

[0050] As used herein, a "pharmaceutically acceptable carrier" or a "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, coating agents, isotonic and absorption retarding agents, surfactants, fillers, disintegrants, association agents, diluents, lubricants, glidants, pH adjusting agents, buffers, enhancers, wetting agents, solubilizers, surfactants, antioxidants, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may contain other active compounds that provide complementary, additional, or enhanced therapeutic functions, and solid carriers or excipients such as lactose, starch, or talc, or liquid carriers such as water, fatty oils, or liquid paraffin.

[0051] The pharmaceutical compositions of the present invention may be administered in any known manner. The term "administering" or "administration of" a substance, compound, or agent to a subject may be performed using one of a variety of methods known to those of skill in the art. For example, the compound or agent may be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through the skin tract). The compound or agent may also be suitably introduced by rechargeable or biodegradable polymeric devices or other devices, such as patches and pumps, or formulations that provide sustained, sustained, or controlled release of the compound or agent. Administration may also be performed, for example, once, multiple times, and / or for one or more extended periods of time. According to some embodiments, the composition is administered once, twice, three times, four times, five times, or six times per day. According to other embodiments, the composition is administered once, twice, three times, four times, five times, or six times per month. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug or have another person administer the drug and / or provides a prescription for a drug to a patient administers the drug to the patient. According to one embodiment, administration of the pharmaceutical composition of the present invention is intranasal administration.

[0052] As defined herein above, the disease or disorder that is treated in a sex-specific manner is the disease or disorder associated with the abnormal functioning of ADNP.Non-limiting examples of such diseases are progressive supranuclear palsy (PSP) and related diseases (CBD, MSA), schizophrenia and related psychiatric disorders (including depression), Alzheimer's disease, amnesic mild cognitive impairment (aMCI), Parkinson's disease, neurodevelopmental disorders (including but not limited to ADNP syndrome, Phelan-McDermid syndrome, Dravet syndrome, Rett syndrome), Angelman syndrome, autism spectrum disorder that is idiopathic or hereditary, Down's syndrome, amyotrophic lateral sclerosis (ALS), ataxia, Huntington's disease, and muscle diseases associated with the abnormal functioning of ADNP (including but not limited to natural aging, Duchenne dystrophy and Pompe disease). All of these diseases or disorders are associated with or mediated by abnormal functioning of the ADNP / cytoskeleton, including aberrant expression, missense, nonsense, and frameshift mutations that result in abnormal length or structure of ADNP.

[0053] PSP According to one embodiment, the disease is progressive supranuclear palsy (PSP).

[0054] The term "progressive supranuclear palsy" or "PSP" refers to a neurological disorder of unknown origin that gradually destroys cells and accumulates abnormal aggregates of the microtubule-associated protein Tau in many regions of the brain, including progressive deterioration of neuronal and glial cells in the midbrain and frontal cortex, which present insoluble paired helical filaments of Tau protein, as described, for example, in Shi et al., Nature 2021, 598:359-363.

[0055] PSP begins with a prodromal phase in which there is an increase in neuropathological abnormalities. Patients then develop a single symptom suggestive of PSP (soPSP). In any of the methods described herein, the PSP can be classical PSP-Richardson's Syndrome (PSP-RS), PSP-Parkinsonism (PSP-P), PSP-corticobasal syndrome (PSP-CBS), PSP-Progressive Non-Fluent Aphasia (PSP-PNFA), or PSP-Pure Akinesia with Gait Freezing (PSP-PAGF) (Ling et al., J. Mov. Discord. 9(1):3:13-2016). After onset, PSP symptoms worsen rapidly and progressively. Subjects diagnosed with PSP can become severely disabled within five years and die within six years. PSP symptoms usually first appear around age 60 and worsen until death. People with PSP typically die from pneumonia, choking, or other complications caused by loss of autonomic and motor function (e.g., ability to swallow) due to loss of functional brain cells.

[0056] Signs and symptoms of PSP include motor, cognitive, and psychiatric disorders. Voluntary movement may be impaired in PSP, including pseudobulbar paralysis (i.e., inability to control facial movements), bradykinesia (i.e., slow or abnormal muscle movements), stiffness of the neck and trunk, gait disturbance, balance disturbance, postural instability, and difficulty speaking and swallowing. The most obvious outward sign of the disease is the inability to adjust and move the eyes normally, resulting in vertical gaze paralysis. Cognitive dysfunction includes loss of executive function (e.g., attention control, inhibitory control, working memory, cognitive flexibility, reasoning, problem solving, and planning) and reduced fluency. Associated psychiatric symptoms include depression, irritability, sadness or lethargy, insomnia, fatigue, and loss of energy. In some embodiments, the subject may be identified as having PSP using the MDS PSP diagnostic criteria (e.g., as described in Hoglinger et al., Mov. Disord. 31:644-652, 2016).

[0057] In some embodiments, a subject may be identified as being at high risk for developing PSP or as having PSP (e.g., any type of PSP described herein), for example, at least in part, by detecting tau protein deposits (e.g., four-repeat tau protein deposits), detecting atrophy of the midbrain and / or superior cerebellar peduncle (e.g., using any of the imaging techniques described herein or known in the art, e.g., Magnetic Resonance Imaging (MRI) or Positron Emission Tomography (PET) scanning), and / or detecting hypometabolism in the frontal cortex, caudate nucleus, and / or thalamus in a subject (e.g., using any of the imaging techniques described herein or known in the art, e.g., MRI, CT scan, or PET scanning).

[0058] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in treating or inhibiting the onset or progression of PSP in a subject in a sex-specific manner. According to one embodiment, the subject is female.

[0059] Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in treating or inhibiting the onset of progressive supranuclear palsy (PSP) in a female subject.

[0060] According to some embodiments, the female subject is 50 years of age or older. According to some embodiments, the female subject is 55 years of age or older. According to some embodiments, the female subject is 60 years of age or older. According to some embodiments, the female subject is 65 years of age or older. According to some embodiments, the female subject is 70, 75, 80, 85, or 90 years of age or older.

[0061] According to some embodiments, the female subject is administered 1-100 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-70 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-65 mg / day, 5-60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day, or about 30 mg / day of NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, 55-65 mg / day, or about 60 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses.

[0062] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating or inhibiting the onset of Progressive Supranuclear Palsy (PSP) in a male subject. According to some embodiments, the male subject is 50 years of age or older. According to some embodiments, the male subject is 55 years of age or older. According to some embodiments, the male subject is 60 years of age or older. According to some embodiments, the male subject is 65 years of age or older. According to some embodiments, the male subject is 70, 75, 80, 85, or 90 years of age or older. According to some embodiments, the male subject is administered 1-50 mg / day of the NAP peptide. According to some embodiments, the subject is administered 1-45 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 2-40 mg / day, or 3-35 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 1-30 mg / day, 5-35 mg / day, 10-40 mg / day, or 10-35 mg / day of NAP peptide. According to some embodiments, the male subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 or 25-35 mg / day, or about 30 mg / day of NAP peptide. According to some embodiments, the male subject is administered 1-15 mg / day, 2-10 mg / day, 3-10 mg / day, 1-5 mg / day, or 2-4 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses.

[0063] According to some embodiments, the efficacy of the treatment may be evaluated by measuring any known symptom or parameter associated with the disease. According to some embodiments, the treatment results in an improvement in one or more of the symptoms of the parameter. Thus, according to some embodiments, the treatment includes an improvement in at least one of the following symptoms associated with PSP: behavior, bulbar cranial nerve nucleus disorder, dysarthria, eye movement, limb movement, and gait. According to other embodiments, the treatment includes an improvement in the score of the Geriatric Depression Scale and / or the Clinical Global Impression of Disease Severity. According to other embodiments, the treatment includes an improvement in the score of the Schwab-England Activities of Daily Living Scale (SEADL).

[0064] The term "improved" when referring to a symptom or parameter of any one of the diseases described in this application may be quantitative and qualitative, as is known in the art. The improvement is measured / assessed in comparison to subjects not receiving the treatment, i.e., a control. Thus, the term may have the meaning that the symptom and / or parameter of a treated individual or patient population is improved by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to an individual or patient population not receiving the therapeutic agent. According to further embodiments, the improvement is at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 5-fold, or at least 10-fold compared to an individual or patient population not receiving the therapeutic agent.

[0065] Schizophrenia According to other embodiments, the disease is schizophrenia. The term "schizophrenia" is well known in the art and refers to mental disorders described, for example, in DSM-IV-TR.

[0066] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in the gender-specific treatment of schizophrenia in a subject.

[0067] According to one embodiment, the subject is female. Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating schizophrenia in a female subject. According to some embodiments, the female subject is administered 1-20 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-15 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. According to some embodiments, the female subject is administered 1-4, 1-3, or 2-4 mg / day of NAP peptide. According to some embodiments, the female subject is administered about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4 mg / day of NAP peptide. According to some embodiments, the female subject is administered about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, or about 4 mg of NAP peptide twice a day (bis in die, bid). According to some embodiments, the female subject is administered 4-5 mg / day, or about 5 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses.

[0068] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating schizophrenia in a male subject. According to some embodiments, the male subject is administered 10-80 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 15-75 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 15-70 mg / day, 20-60 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 20-40, or 25-35 mg / day. According to some embodiments, the male subject is administered 25-60 mg / day, or 30-50 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 40-80 mg / day, 50-70 mg / day, or 55-65 mg of the NAP peptide. According to some embodiments, the male subject is administered about 30, about 40, about 50, or about 60 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses.

[0069] amnestic mild cognitive impairment (aMCI) In other embodiments, the disease is amnestic mild cognitive impairment (aMCI). The term "amnestic mild cognitive impairment" refers to mild cognitive impairment with memory loss as the main symptom, and is often seen as a prodromal stage of Alzheimer's disease. For example, a person may begin to forget important information that they would have previously easily remembered, such as appointments, conversations, or recent events.

[0070] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in the gender-specific treatment of aMCI in a subject.

[0071] According to one embodiment, the subject is female. Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating aMCI in a female subject. According to some embodiments, the female subject is administered 20-80 mg / day of NAP peptide once or twice daily. According to some embodiments, the female subject is administered 25-70 mg / day, or 30-70 mg / day of NAP peptide. According to some embodiments, the female subject is administered 35-75 mg / day, 40-70 mg / day, or 40-65 mg of NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 50-70 mg / day, or 55-65 mg of NAP peptide. According to some embodiments, the female subject is administered about 30, about 35, about 40, about 45, about 50, about 55, or about 60 mg / day of the NAP peptide.

[0072] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating aMCI in a male subject. According to some embodiments, the male subject is administered 10-80 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 15-75 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 15-70 mg / day, 20-60 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 20-40, or 25-35 mg / day. According to some embodiments, the male subject is administered 25-70 mg / day, or 30-70 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 35-75 mg / day, 40-70 mg / day, or 40-65 mg of the NAP peptide. According to some embodiments, the male subject is administered 40-80 mg / day, 50-70 mg / day, or 55-65 mg of NAP peptide. According to some embodiments, the male subject is administered about 30, about 35, about 40, about 45, about 50, about 55, or about 60. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses.

[0073] Patients at risk for Alzheimer's disease In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in the sex-specific prevention of Alzheimer's disease.

[0074] Alzheimer's Disease In other embodiments, the disease is Alzheimer's disease. The term "Alzheimer's disease" refers to a progressive neurological disorder of the brain that results in irreversible loss of nerve cells and dementia. The clinical hallmarks of Alzheimer's disease are progressive impairments in memory, judgment, decision-making, orientation to the physical environment, and language.

[0075] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutical acceptable carrier for use in the sex-specific treatment of Alzheimer's disease in a subject.

[0076] According to one embodiment, the subject is female. Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating Alzheimer's disease in a female subject. According to some embodiments, the female subject is administered 1-80 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-70 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-65 mg / day, 5-60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day or 25-35 mg / day of NAP peptide, or about 30-35 mg / day of NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, 55-65 mg / day, or about 60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 1-20 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-15 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. According to some embodiments, the female subject is administered 4-5 mg / day, or about 5 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into several doses, for example, two, three, or four doses. According to one embodiment, the dose of NAP peptide is about 5 mg once a day, or about 15 mg twice a day.

[0077] In some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating Alzheimer's disease in a male subject. According to some embodiments, the male subject is administered 5-30 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 1-80 mg / day of the NAP peptide. According to some embodiments, the subject is administered 1-70 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 2-65 mg / day, 5-60 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, 55-65 mg / day, or about 60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 1-20 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-15 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. According to some embodiments, the female subject is administered 4-5 mg / day, or about 5 mg / day of NAP peptide.

[0078] According to any one of the above embodiments, Alzheimer's disease is in an early stage of the disease. According to some embodiments, the subject is in a prodromal stage of the disease. Thus, in some embodiments, the present invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in the sex-specific prevention of Alzheimer's disease in a male subject. According to some embodiments, the subject is pre- or post-onset of Alzheimer's disease and is characterized by at least one of the following biomarkers in a biological sample: (i) abnormal P53 protein, (ii) P-tau217, (iii) P-tau231, and (iii) P-tau181, and (iv) changes in ADNP expression, e.g., as described in US2010303785. The term "biological sample" encompasses various sample types obtained from an organism that can be used in diagnostic or monitoring assays. The term encompasses blood, serum, other liquid samples of biological origin, solid tissue samples such as biopsy specimens, or tissue cultures or cells derived therefrom, and their progeny. The term specifically encompasses clinical samples, including biological fluids including serum, plasma, urine, and in the case of ocular samples, aqueous humor and vitreous, as well as tissue samples. The term also encompasses samples that have been manipulated in any way after treatment with reagents, solubilization, or enrichment for specific components, etc.

[0079] The biological sample may be a blood or serum sample. Treatment according to some embodiments is initiated before clinical signs of Alzheimer's disease appear. According to some embodiments, treatment comprises improving Geriatric Depression Scale scores in subjects with Alzheimer's disease.

[0080] In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is a muscle disorder associated with or mediated by abnormal functioning of ADNP. In some aspects, the present invention provides a pharmaceutical composition comprising NAP and a pharmaceutically acceptable carrier for use in treating a disease or disorder in a female subject. In some embodiments, the female subject is administered 1-80 mg / day of NAP peptide. In some embodiments, the subject is administered 1-70 mg / day of NAP peptide. In some embodiments, the female subject is administered 2-65 mg / day, 5-60 mg / day of NAP peptide. In some embodiments, the female subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day of NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, 55-65 mg / day, or about 60 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 1-20 mg / day of the NAP peptide. According to some embodiments, the subject is administered 1-15 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 2-10 mg / day, 3-8 mg / day of the NAP peptide. According to some embodiments, the female subject is administered 4-5 mg / day, or about 5 mg / day of the NAP peptide. In some embodiments, the invention provides a pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (NAP peptide) and a pharma- ceutically acceptable carrier for use in treating a disease or disorder in a male subject. According to some embodiments, the male subject is administered 1-80 mg / day of the NAP peptide. According to some embodiments, the male subject is administered 1-70 mg / day of NAP peptide. According to some embodiments, the male subject is administered 2-65 mg / day, 5-60 mg / day of NAP peptide. According to some embodiments, the male subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day of NAP peptide.According to some embodiments, the male subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, or 55-65 mg / day, or about 60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 1-20 mg / day of NAP peptide. According to some embodiments, the male subject is administered 1-15 mg / day of NAP peptide. According to some embodiments, the male subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. According to some embodiments, the male subject is administered 4-5 mg / day or about 5 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into multiple doses, for example, two doses, three doses, or four doses.

[0081] According to yet another aspect, the present invention provides a pharmaceutical composition comprising a NAP peptide and a pharma- ceutical acceptable carrier for use in ameliorating and / or preventing side effects of anti-amyloid beta therapy, wherein the therapy comprises an anti-amyloid beta antibody.

[0082] As used herein, the term "anti-amyloid-β antibodies" refers to antibodies that specifically bind to amyloid-β and are used to treat Alzheimer's disease. According to some embodiments, the anti-amyloid-β therapy is selected from aducanumab, bupineuzuman, gantenerumab, gantenerumab, lecanemab, and solanezumab. According to some embodiments, the anti-amyloid-β therapy is aducanumab.

[0083] According to some embodiments, the composition is administered in a gender-specific manner. According to some embodiments, the subject is female. According to some embodiments, the composition is administered to a female subject. According to some embodiments, the female subject is administered 1-80 mg / day of NAP peptide. According to some embodiments, the subject is administered 1-70 mg / day of NAP peptide. According to some embodiments, the female subject is administered 2-65 mg / day, 5-60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day of NAP peptide. According to some embodiments, the female subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, 55-65 mg / day, or about 60 mg / day of NAP peptide. According to some embodiments, the female subject is administered 1-20 mg / day of NAP peptide. In some embodiments, the subject is administered 1-15 mg / day of NAP peptide. In some embodiments, the female subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. In some embodiments, the female subject is administered 4-5 mg / day, or about 5 mg / day of NAP peptide.

[0084] According to some embodiments, the subject is male. In some embodiments, a pharmaceutical composition comprising a NAP peptide is administered to a male subject. According to some embodiments, the male subject is administered 1-80 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 1-70 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 2-65 mg / day, 5-60 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 10-50 mg / day, 15-45 mg / day, 20-40 mg / day, or 25-35 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 40-80 mg / day, 45-75 mg / day, 50-70 mg / day, or 55-65 mg / day, or about 60 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 1-20 mg / day of a NAP peptide. According to some embodiments, the male subject is administered 1-15 mg / day of NAP peptide. According to some embodiments, the male subject is administered 2-10 mg / day, 3-8 mg / day of NAP peptide. According to some embodiments, the male subject is administered 4-5 mg / day or about 5 mg / day of NAP peptide. According to any one of the above embodiments, administration may be in a single dose or may be divided into multiple doses, for example, two doses, three doses, or four doses.

[0085] According to any one of the above embodiments, the use includes administering the pharmaceutical composition at least one day before starting the anti-amyloid beta therapy. According to any one of the above embodiments, the use includes administering the pharmaceutical composition at least 2, 3, 4, 5, 6, or 7 days before starting the anti-amyloid beta therapy. According to any one of the above embodiments, the use includes administering the pharmaceutical composition at least 2, 3, 4, 5, 6, 7, or 8 weeks, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months before starting the anti-amyloid beta therapy.

[0086] According to some embodiments, the use comprises administering the pharmaceutical composition in combination with an anti-amyloid beta therapy.

[0087] According to yet another aspect, the present invention provides a method for treating or inhibiting the onset or progression of a disease or disorder associated with abnormal functioning of action-dependent neuroprotective protein (ADNP) in a subject, wherein the treatment is gender-specific.

[0088] According to yet another aspect, the present invention provides a method for treating or inhibiting the onset or progression of progressive supranuclear palsy (PSP) in a female subject, comprising administering a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO:1).

[0089] According to yet another aspect, the present invention provides a method for treating or inhibiting the onset or progression of progressive supranuclear palsy (PSP) in a male subject, the method comprising administering 1 to 50 mg / day of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO:1).

[0090] According to yet another aspect, the present invention provides a method for treating schizophrenia in a male subject, comprising administering 10 to 80 mg / day of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1).

[0091] According to yet another aspect, the present invention provides a method for treating or suppressing the onset or progression of aMCI in a male subject, the method comprising administering 20 to 80 mg / day of a peptide comprising the amino acid sequence NAPVSIPQ (sequence number 1).

[0092] According to yet another aspect, the present invention provides a method for treating or suppressing the onset or progression of aMCI in a female subject, the method comprising administering 35 to 80 mg / day of a peptide comprising the amino acid sequence NAPVSIPQ (sequence number 1).

[0093] According to yet another aspect, the present invention provides a method for preventing the onset of Alzheimer's disease, preferably in a gender-specific manner / type.

[0094] According to yet another aspect, the present invention provides a method of treating schizophrenia in a female subject, comprising administering 1 to 4 mg / day of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO:1).

[0095] According to yet another aspect, the present invention provides the use of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1) for the preparation of a medicament for sex-specifically treating or inhibiting the onset or progression of a disease or disorder associated with abnormal functionality of action-dependent neuroprotective protein (ADNP) in a subject.

[0096] According to yet another aspect, the present invention provides the use of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1) for the preparation of a medicament for treating or inhibiting the onset or progression of progressive supranuclear palsy (PSP) in a female subject.

[0097] According to yet another aspect, the present invention provides use of a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1) for the preparation of a medicament for treating schizophrenia in a male subject, the treatment comprising administering a medicament comprising administering 15 to 80 mg / day of the peptide.

[0098] According to any one of the embodiments and aspects of the present invention, the treatment using NAP may be combined with any treatment commonly used for the corresponding disease.

[0099] The invention will now be described with reference to the following non-limiting examples.

[0100] Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the invention.

[0101] The terms "a," "an," and "the" are used interchangeably herein to mean one or more.

[0102] The term "and / or" is used to indicate that either or both of the stated cases may occur; for example, A and / or B includes (A and B) as well as (A or B).

[0103] The term "or" is used herein to indicate alternatives that may be combined where appropriate, i.e., the term "or" includes each listed alternative separately as well as combinations thereof where such combinations are not mutually exclusive.

[0104] The terms "comprising", "comprise(s)", "including, including(s)", "having", "has" and "contain(s)" are used interchangeably herein and have the meaning of "consisting at least in part of". When interpreting each description in this specification that includes the term "comprising", other features or features beginning with this term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in a similar manner. The terms "have", "has", "having" and "comprising" may also include and may be replaced by the meanings "consisting of" and "consisting essentially of". Thus, the term "comprising the amino acid sequence" includes and may be replaced by the term "consisting of the amino acid sequence". The term "consisting of" excludes any component, step, or procedure not specifically delineated or listed. The term "consisting essentially of" means that the composition or component may contain additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed composition or method.

[0105] As used herein, the term "about" when referring to a measurable value, such as an amount, temporal duration, etc., is intended to encompass a variation of + / - 10%, or + / - 5%, + / - 1%, or + / - 0.1% from the specified value. EXAMPLES

[0106] Example 1. NAP for gender-specific treatment of progressive supranuclear palsy method In this example, we used the results of a clinical trial conducted as described in Boxer et al. Then, in a double-blind, parallel-group, phase 2 / 3 study, participants were randomly assigned 1:1 to permuted blocks at 48 sites in Australia, Canada, France, Germany, the UK, and the US to receive davunetide (NAP, with the amino acid sequence NAPVSIPQ shown as SEQ ID NO: 1, 30 mg intranasally twice daily) or placebo for 52 weeks. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. The primary endpoints were the change from baseline in the PSP Rating Scale (PSPRS, 28 items, 6 categories, 0=normal, 100=mostly impaired) and Schwab England Activities of Daily Living Scale (SEADL, 11-point rating scale, 0=resting, 100%=fully independent, 10% increments) to 52 weeks. Data collection occurred at weeks 0, 6, 13, 26, 39, and 52. All participants and study personnel were masked to treatment assignment. Analyses were by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. 313 participants were randomly assigned to davunetide (n=157) or placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). Secondary outcomes were ventricular volumes measured by boundary shift integral analysis of T1-weighted magnetic resonance imaging (MRI) scans, most of which were collected at weeks 0 and 52. Concurrently, selected patients also underwent lumbar puncture to assess tau content and tau hyperphosphorylation in cerebrospinal fluid (CSF). Boxer et al. concluded that davunetide is not an effective treatment for PSP and that clinical trials of disease-modifying therapies are feasible in patients with PSP and should continue with other promising tau-directed therapies.

[0107] To further understand disease progression, sex / age / baseline differences and drug effects, we re-evaluated the study results, separating men and women, and evaluating the primary and secondary endpoints. In this regard, we further evaluated the six impairment domains of the PSPRS from the https: / / www.physio-pedia.com / Progressive_Supranuclear_Palsy_Rating_Scale_(PSP-RS) individually, namely daily activities (7 items with a total maximum score of 24, depending on medical history), behavior (mental, emotional, interference with activities of daily living, maximum score of 16), bulbar cranial nerve nuclei (speech and swallowing, maximum score of 8), eye movement (eye and eyelid activity, 16 points), limb movement (fine motor skills including tremor, 16 points), and gait / midline (general motor skills, 20 points).

[0108] Statistical Considerations: To include ventricular volume measurements, cohorts consisted of female and male PSP patients treated with davunetide or placebo (sample sizes per gender and treatment group: 48-55 over 52 weeks of treatment), and outcome variables included ventricular volumes (referred to as volume), PSPRS, and SEADL assessed at study entry and followed up to week 52 after twice-daily dosing.

[0109] Data analysis was performed using Graph Pad Prism 7.0 software (see Figures 1 and 4). Other statistical tests and visualizations were performed in R version 4.2.1 (2022-06-23) using the base library, ggplot2 and ggplot2 extension packages. Correlation plot statistics (Figures 2, 3, and 5) were calculated using the standard Pearson method. Volume change (from Figure 3) is the difference between baseline and week 52 measurements. PSPRS, SEADL, and ventricular volumes in the figure (Figure 5) are expressed by the difference between baseline and week 52 measurements as a percentage of the baseline measurement. Figures 6 and 7 show absolute changes over time due to non-normal distribution of most parameters, and statistical significance was measured using the Wilcoxon test. (3-fold difference from penultimate upper / lower quantiles) * Only extreme values ​​(defined as IQR deviations) were excluded from the final calculations. Only 11 observations were considered extreme, and their impact on our results was not significant. Figure 8 represents the Geriatric Depression Scale (GDS) and was created using excel.

[0110] result Significant baseline gender differences Figure 1 reveals that at baseline, the studied populations differed by weight and height, with clearly higher values ​​in men. Furthermore, on average, randomized women in the davunetide group showed significantly increased weight compared to the placebo group. There were no differences with regard to age.

[0111] Focusing on brain structure, as expected from previous evaluations, MRI measurements of ventricular volumes were larger at baseline in men compared to women tested, suggesting that sex separation in the analysis of results is necessary for neuroprotective drug trials, regardless of the original design.

[0112] No differences were found in baseline measurements of the PSPRS and Schwab England ADL (SEADL) scales. However, closer examination (Student's t test, one-tailed) of sex-specific davunetide vs. placebo comparisons showed trends toward increases in mean ventricular volume and PSPRS measurements (P = 0.0716 and P = 0.0934, respectively) and decreases in SEADL measurements (P = 0.0934) in women only, potentially indicating an unfavorable starting point for women receiving davunetide vs. placebo (Figure 1D-F).

[0113] Davunetide treatment provides significant neuroprotection against age- / ventricular volume-dependent increases in female patients with PSP Considering the significant gender and age differences in ventricular volume, the target of davunetide is neuroprotection, and we first focused on the percentage of baseline ventricular volume change with age for davunetide protective effect. Placebo group showed no difference in the percentage of ventricular volume increase during the study period (52 weeks) across age groups, i.e., there was a certain deterioration, but davunetide administration showed a significant neuroprotective effect in elderly female patients (Figure 2). In men, no difference was observed between the davunetide group and the placebo group (Figure 2). Thus, the variation of ventricular volume change in davunetide-administered men across age groups during the study period (52 weeks) was comparable to that of the placebo group, but a significant difference in ventricular volume change compared to the placebo group was observed for davunetide-administered women, indicating its neuroprotective effect in elderly female patients (Figure 2). Focusing further on age, the most beneficial davunetide effect was found in women over 60 years old. Thus, we found a significant age / ventricular volume reduction correlation in women receiving davunetide (r=-0.5, P=0.0001) (Figure 2), whereas male patients showed no benefit. Furthermore, Figure 3, which separates the study population by gender and baseline ventricular volume measurements, shows a dramatic increase in placebo group that correlated with baseline ventricular volume (r=0.74, b, P=2.36). -9), and in women, davunetide treatment was completely protective. In contrast to women, the male cohort showed no dependence on baseline ventricular volume measurements and no drug effect (Figure 3).

[0114] Similar results were seen at the overall population level (Student's t test, two-tailed, * P=0.04 and -#P=0.056, Wilcoxon test, davunetide protection for women). Exploratory results looking at very small numbers of individuals also showed that the female cohort also showed a trend towards reduced total and phosphorylated tau in cerebrospinal fluid (CSF) in patients receiving davunetide compared to placebo (Figure 4), experiments were performed as detailed in Rojas et al. (Neurology 2018, 90(4):e273-e281).

[0115] Davunetide neuroprotection correlated significantly with the study's primary endpoints: SEADL and PSPRS FIG. 5 shows correlation plots of percent change compared to baseline in davunetide versus placebo outcomes at week 52, including the study's primary endpoints PSPRS and SEADL, secondary endpoints ventricular volume change, and age.

[0116] The disease course in men also appeared to differ from women in the fact that the only significant correlations seen in men were with baseline age and SEADL change in the davunetide group (Figure 5).

[0117] Furthermore, consistent with the results above (Figure 2), ventricular volume was significantly correlated with age only in women (r = -0.505 *** This female-specific davunetide protection against ventricular volume was consistent with the study's primary endpoint, SEADL, r=-0.298. * , and PSPRS (nearly significant, r = 0.272, for placebo group only), indicating davunetide neuroprotection, which translated into clinical protection. Furthermore, SEADL and PSPRS percent change from baseline to week 52 were further correlated in the female group (r = -0.403** , placebo, and r = -0.347 * , davnetide).

[0118] Significant gender differences and protection against SEADL deterioration with davunetide treatment in women Given the observed gender differences in ventricular volumes, with a dramatic volume increase correlating with baseline levels in placebo-treated women only, and davunetide protection (Figure 3), we examined clinical disease progression in women and men separately. Figure 6 shows the changes in the PSPRS over time, i.e., 6, 13, 26, 39, and 52 weeks after study initiation in the placebo group, defining disease progression. Significantly accelerated disease progression was observed in women, nearly reaching significance at week 52 (#P=0.05, Figure 6A). The PSPRS measures impairment across 28 items in six domains: daily activities (by history), behavior, bulbar cranial nerve nuclei, eye movement, limb movement, and gait / midline. Thus, we also examined six different domains, with the following at weeks 26 and 52, respectively: * We found significant differences between males and females in limb motor activity (fine motor skills) with P = 0.03 and 0.02 (Figure 6B). These findings indicate a gender-dependent disease progression. Figure 6C further shows that the difference in limb motor activity (fine motor skills) was already significant at week 13 ( ** P = 0.01), showing a dramatic difference in continued deterioration of SEADL between men and women.

[0119] Looking at efficacy in men, davunetide treatment showed significant increases in PSPRS and significant decreases in SEADL from week 26 compared to placebo, mimicking more rapid disease progression in women (Figure 6D).

[0120] In contrast, in women, davunetide treatment resulted in PSPRS measurements that tended towards significant improvement at 52 weeks (Figure 7A). A temporary adverse effect on oculomotor activity was detected at week 6 (P=0.0127). However, no adverse effects were observed for all other PSPRS domains. Interestingly, a significant deterioration in mental behavior was found in women in the placebo group ( *** r=0.18, P=0.000388, measures of disorientation, mental retardation including slow thought processes and inattention, emotional incontinence and grasping behaviors affecting activities of daily living), with davunetide treatment the progression of the disease was almost halted, indicating improvement of the disease (#r-0.092, P=0.0705, Fig. 7B). Furthermore, a significant protective effect was found on the bulbar brain nerve nucleus domain of the PSPRS. At 52 weeks of treatment, davunetide protected against dysarthria, a speech disorder caused by brain injury resulting in loss of control of the muscles used in speech, and dysphagia, difficulty swallowing (Fig. 7C, * P=0.0222). Moreover, limb motor skills deteriorated faster in women versus men (Figure 6B) and were partially protected by davunetide administration in women (#P=0.0838). Finally, davunetide efficacy in women was abnormal in SEADL (change from baseline), showing a significant protective effect starting at week 39 and continuing at week 52 (Figure 7D, respectively). * P=0.0187 and ** P=0.00537). Thus, we found that female-specific target involvement and protection against increases in ventricular volume was associated with significant protection against bulbar cranial nerve nucleus functional activity, without significant deterioration of mental activity within the PSPRS correlated with activities of daily living (SEADL).

[0121] Additionally, we reassessed an additional secondary outcome measure, CGIC (Clinical Global Impression of Change).Exploratory outcomes included CGIds (Clinical Global Impression of Disease Severity), GDS (Geriatric Depression scale), and RBANS (Repeatable Battery for the Assessment of Neuropsychological Disease Severity).

[0122] Calculating the 52-week change as a proportion of the baseline measurement, and extending the analysis to the first additional secondary endpoint, CGIC, showed a significant correlation with SEADL (r=-0.306 for women receiving davunetide and placebo, respectively). * , -0.304 * , and -0.307 for male placebo * CGIds was most significantly correlated with SEADL (r = -0.470 for davunetide and placebo, respectively, in women). *** and -0.408 ** , and placebo for men -0.301 ** CGIds were also highly correlated with patient age for the female placebo group and the male davunetide group (r = -0.483, respectively). *** and -0.421 ** Age also correlated well with CGIC in the davunetide group in men (-0.331 * Consistent with the above results, CGIds also correlated with ventricular volume only in the female placebo group (0.405 ** The GDS score correlated only in the female placebo group, almost significantly with ventricular volume (r=0.253), and significantly with CGIds and SEADL (r=0.323, respectively). * , -0.310 *), which showed a correlation. In this regard, the Wilcoxon test showed that GDS scores (measuring geriatric depression) improved significantly in women who received davunetide compared to placebo at week 52, but * P = 0.023), whereas there was a highly significant gender difference in the placebo group ( ** P = 0.007) (Figure 8). In contrast, CGIds showed a gender-dependent difference in the davunetide treatment groups (P = * 0.02), and worsened only in men receiving davunetide ( * P=0.013).

[0123] Other exploratory endpoints showed additional significant correlations; for example, phonemic fluency was most significantly correlated with CGIds only in the female placebo group, consistent with davunetide protection (r=0.447 ** In contrast, for males, phoneme fluency was significantly higher for letter-number sequences (r = 0.556 *** Davunetide, r=0.419 ** placebo) and the GDS and SEADL of the placebo group (r = 0.306, respectively) * , 0.281 * ) were mostly correlated with CGIC. Letter number sequencing correlated with CGIC only in men who received davunetide (r = 0.288 * The Color Trails2 test, a neuropsychological assessment of executive function (Boxer et al.), tended toward a correlation with CGIC in the female davunetide group (r=0.254).

[0124] Consideration A surprising female-specific PSP-associated neurodegeneration was observed in this study as an increase in ventricular volume (depending on baseline starting point). Thus, we found a gender-dependent differential vulnerability of ventricular volume measurements, indicating accelerated neurodegeneration in female PSP patients compared to males. We also found differential disease progression in males and females, with females progressing faster in what appears to be a deterioration of fine motor skills. Furthermore, the brains of PSP female patients respond to davunetide administration and require neuroprotection differently from the brains of PSP males, as seen in an age- and baseline dose-dependent manner, and davunetide protects microtubule cytoskeleton interactions, brain structure, and axonal transport regulated by ADNP in a gender-dependent manner.

[0125] Entering within one year of disease onset, lethargy and executive dysfunction are more frequent in female PSP patients, and the time to slurred speech, severe dysphagia, and cognitive impairment is earlier in women, which correlates with SEADL correlation with ventricular volume in women but not in men, male-female differences in SEADL progression, and davunetide bulbar nerve nucleus protection in women in the current study.

[0126] These findings highlight the need for appropriate drug and dose selection for the study population.

[0127] Nevertheless, the correlation between behavioral outcomes and ventricular volume protection is highly significant. A very recent review cited progressive, dose-dependent ventricular enlargement in the brains of early Alzheimer's disease patients treated with the FDA-approved drug aducanumab (anti-amyloid-β therapy) (Ayton S. Nature reviews Neurology 2022, 18(7):383-384). Our current findings imply that davunetide protects against this potentially undesirable side effect of amyloid-targeting drugs, as well as against disease-related ventricular volume loss, presenting the first of its kind of drug with demonstrated human efficacy in a select population of women suffering from PSP and beyond. The improvement in GDS=Geriatric Depression Scale in women with PSP indicates that the treatment may be effective for the same indications in subjects with Alzheimer's disease as well as geriatric depression, which is a major risk for Alzheimer's disease depression, given the common mechanisms behind these diseases, and further indicates a gender-dependent dosing regimen for the treatment of depression in general.

[0128] Example 2. Prevention of Alzheimer's disease neurodegeneration Computational analysis using eukaryotic linear motif (ELM) prediction tools identified several caspase cleavage sites in ADNP, including those from the following classes: cysteinyl aspartate-specific proteases, subtilisin-like proprotein convertases (PCSK), mammalian subtilisin / kexin isozymes (SKI), and basic amino acid pair cleavage system 4 (SPC4).

[0129] Caspases play important roles in apoptosis (cell death), development, and differentiation. Caspases recognize their respective substrates by a specific cleavage motif. There are five amino acids of the substrate surrounding the caspase cleavage site, named (N- to C-terminus): P4, P3, P2, P1, P-1. The scissile bond (usually a small amino acid) between the essential aspartic acid in P1 and P-1 is cleaved by caspases-3 and -7, but the P4 position relative to P-1 is important for substrate specificity and recognition.

[0130] We found that ADNP residues 734-738 contain the motif DDSDS, which is a recognition motif for caspase-3 and caspase-7. Cleavage of caspase substrates results in the characteristic morphological properties of apoptotic cell death, including membrane blebbing, nuclear condensation, cell rounding, and the formation of apoptotic vesicles. Thus, activated caspase-3, a key enzyme in the apoptotic pathway, is often used as a marker for apoptotic cells. The length of the ADNP protein after caspase cleavage is 737 aa. Interestingly, p.Arg730 * One of the most common autism / intellectual disability-causing de novo mutations in ADNP in humans is closely located near a caspase cleavage site. Furthermore, one of the pathogenic mutations in aging / Alzheimer's disease-associated ADNP is the recurrent somatic ADNP frameshift mutation p.Arg730Thrfs. * 4 cleaves ADNP long into a 734 aa protein.

[0131] Subtilisin-like proprotein convertases (PCSKs) (mammalian subtilisin / kexin isozymes SKs) are widely expressed in mammalian neuronal and endocrine cells and play a major role in the proteolytic processing of both neuropeptide and peptide hormone precursors. Members of the subtilisin-like family are proprotein convertases that process latent precursor proteins into biologically active products. PCSK1 (proprotein convertase 1, NEC1) and PCSK2 (proprotein convertase 2, NEC2) are type I proinsulin processing enzymes that are important in the regulation of insulin biosynthesis. These enzymes are also known to cleave proopiomelanocortin, prorenin, proenkephalin, prodynorphin, prosomatostatin, and progastrin.

[0132] We determined that ADNP residues 367-371KQLLP contain a cleavage motif recognized by members of the subtilisin-like family. The length of ADNP after cleavage at this site is 367 aa. Interestingly, the truncating mutation p.Ile359Thrfs * The length of ADNP after 8 is 367 aa and is found in postmortem Alzheimer's disease brains.

[0133] PACE4 (paired basic amino acid cleavage system 4, SPC4) is a calcium-dependent serine endoprotease that can cleave precursor proteins at basic amino acid pair processing sites (e.g., p.Lys20 * ( , found in postmortem Alzheimer's disease brains). Its substrates include transforming growth factor beta-related protein, proalbumin, as well as von Willebrand factor and various neuropeptides. In addition, several basic amino acid pairs are found in ADNP.

[0134] Consideration Previous studies have shown that the short active motif NAP in ADNP protects against activated caspase 3-related apoptosis. Our findings, together with previous observations, suggest that ADNP cleavage by caspase 3 may be harmful at two levels: 1) enhancing DNA damage, and 2) reducing ADNP-tau-microtubule interaction, resulting in tauopathy, followed by or in parallel with apoptosis. These findings imply that ADNP is part of the apoptosis pathway in neuronal cells.

[0135] Also interesting and relevant is the finding that caspase 3-dependent proteolytic cleavage of Tau leads to neurofibrillary tangles and cognitive impairment during normal aging. This is coupled with the discovery of plasma P-Tau217 levels increasing during the early preclinical stages of Alzheimer's disease, where insoluble Tau aggregates are still not detectable by Tau positron emission tomography (PET), indicating an early biomarker. However, an even earlier biomarker has been suggested in unfolded conformational variants of P53 that are evident at least 6 years before disease onset. Phosphorylated Tau and modified P53 in prodromal Alzheimer's disease are also associated with ADNP, which was found to be the only protein decreased in serum samples from Alzheimer's patients, and with ADNP serum levels correlating with intelligence in cognitively unimpaired healthy older adults. Importantly, ADNP indirectly interacts with Sirtuin 1 (SIRT1) at the chromatin and microtubule / tau levels, as well as regulating Forkhead Box O3 (FOXO3), two key genes associated with healthy aging.

[0136] Taken together, our studies suggest ADNP-directed therapy in affected individuals who exhibit one or more of modified P53 biomarkers, P-tau217 and phosphorylated tau in body fluids and identified by imaging. A suggested therapy would be intranasal NAP (davunetide) administration, with previous human experience and cognitive score protection / enhancement in amnesic mild cognitive impairment (aMCI) patients.

[0137] Interestingly, when ADNP (the parent protein of NAP peptides) was specifically analyzed in the RNA sequencing results (Wang et al., J Clin Invest. 2022, 132(2):e149904), the inventors now found a statistically significant increase in its expression only in Alzheimer's disease samples versus controls (approximately 70-80 samples per group) and only in the temporal cortex. Specifically, the FDR (False Discovery Rate) for the temporal cortex showed a very high significance (0.0008) for higher ADNP expression in Alzheimer's disease samples compared to controls.

[0138] Example 3. Gender-specific treatment of amnesic mild cognitive impairment. Consistent with the above examples, the inventors analyzed the results of aMCI clinical trials (Gozes et al., Curr Alzheimer Res. 2009, 6(5):455-60; Morimoto et al., Dement Geriatr DisDisord. 2013, 35(5-6):325-36.), which tested the effect of NAP peptides on subjects suffering from amnesic mild cognitive impairment (aMCI), a precursor to Alzheimer's disease (AD). Reanalyzing the results, the inventors surprisingly found gender-related differences when separating males and females and testing efficacy by the CANTAB Delayed Match-to-Sample DMTS test. DMTS is a test of delayed and recognition memory using simultaneous and delayed visual matching to sample. In this task, subjects are presented with complex visual patterns on a screen, and after a delay (simultaneous, 0, 4, or 12 seconds), four patterns are displayed. The subject's task is to select the pattern that matches the original specimen, depicted here after a 12-second interval. Thus, subjects suffering from aMCI were treated with intranasal davunetide administration (one or three puffs of the same strength davunetide solution) at either 5 mg per day or 15 mg twice daily (BID). Treatment was for 12 weeks, with testing at baseline and every 4 weeks (including 4 weeks after cessation of treatment). When analyzing the data, we separated men and women for the first time, as outlined below. 76 women were divided into three groups (25 or 26 women per group, the placebo group was approximately half and received the same placebo (drug-free formulation) volume, and the other two groups received NAP peptide (davunetide, AL-108)). In parallel, a similarly divided group of 68 men was tested. Of note, all previous analyses did not distinguish between men and women. Now, when men and women are analyzed separately, our new surprising result is an r of -0.409 for women in the placebo group. 2 and r of 0.3217 for men. 2for women receiving davunetide at 15 mg twice daily. 2 = 0.4291 and r for men 2 = 0.7538 (showing gender differences, FIG. 9). Furthermore, Student's t-tests at all study time points showed a significant difference at study week 8 and a trend at weeks 4 and 16 in men only, further contrasting the PSP results and highlighting surprising gender / disease differences. We show that treatment of men with 30 mg / day of NAP peptide provided a statistically significant effect not observed or predicted in previous publications. We further conclude that much higher doses are required, especially in women. As such, doses of 60-80 mg / day of NAP are suggested.

[0139] Example 4. Gender-specific treatment of schizophrenia Javitt et al. (Schizophrenia research 2012, 136(1-3):25-31) showed that NAP (davunetide) provided protection in the UCSD Daily Living Skills Assessment (UPSA) in patients with schizophrenia. Briefly, 63 subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg / day) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. Cognitive effects were assessed with the MATRICS Consensus Cognitive Assessment Battery (MCCB). Functional ability was assessed with the UCSD Daily Living Skills Assessment (UPSA) with a maximum score of 100 and the Schizophrenia Cognition Rating Scale (SCoRS). Subjects continued their current antipsychotic treatment for the duration of the study. For the UPSA, there was a significant main effect of treatment across study arms (p=.048). Between-group effect size (d) values ​​were 0.74 and 0.48 in favor of the 5 and 30 mg doses, respectively. Given that the data were mixed for men and women, it was hypothesized that no differences would be observed between the sexes.

[0140] Considering the results obtained on the involvement of PSP and ADNP in both diseases, we analyzed the data separately for men and women with 7 to 16 subjects per group. We found a surprising and significant difference in the sex groups administered 5 mg daily ( * P=0.0276). Thus, treated women had a mean of 14.9 points (a 15% improvement after 12 weeks), while men trended toward a mean improvement of 7.4 points (Figures 10A and 10C, respectively). Further surprises included the unexpected finding that increasing the dose in women had a significantly less effect on UPSA; that is, at week 12, women receiving 5 mg / day were significantly better than women receiving 15 mg / bid (Figures 10A vs. 10B, *** P=0.002). Overall, the 5 mg daily dose was beneficial for women, as detected after 6 and 12 weeks of treatment. The same low dose was similarly effective in men, especially after 6 weeks of treatment (FIG. 10C), but the 15 mg / bid dose showed surprising, significant results only in men treated for 12 weeks (FIG. 10D). This contradicts Javitt's statement that 15 mg / bid was not significantly effective against UPSA.

[0141] Returning to women, the surprising results suggest that doses of davunetide below 5 mg per day are effective, making a strong case for gender differences. Taking into account the bell-shaped response, we conclude that doses below 5 mg per day, and as low as 1-4 mg per day, provide maximal efficacy in the treatment of schizophrenia in women.

[0142] Linear regression analysis of age (42–56 years) versus UPSA change revealed the most effective dose in women, i.e., 5 mg / day for 12 weeks, (R 2 = 0.2356) and, surprisingly, there was a clear increase in the positive drug effect in older women, arguing for a previously unseen age / efficacy effect.

[0143] Example 5 In this experiment, we analyzed hippocampal RNA sequencing of Adnp mutant (designated HTR(Tyr)) mice exhibiting tauopathy (Karmon et al., Biol Psychiatry. 2022, 92(1):81-95). In this model, gait disorders were accentuated in females and improved by NAP administration. We found a striking mirror image in the brain (hippocampus) action of the NAP peptide (davunetide) in treated mice as a dependency on the sex of the mice. Here, we show for the first time a sex-specific inverse expression of Hace1 (HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1) as a result of NAP administration (Figure 11). Hace1 is associated with ataxia and Huntington's disease, and is also involved in depression and Alzheimer's disease. NAP protection (Figure 11) further validates a sex-dependent treatment of diseases related to or mediated by Hace1.

[0144] While the present invention has been described hereinabove in its preferred embodiments, modifications can be made thereto without departing from the spirit and nature of the invention as defined in the appended claims.

Claims

1. A pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1, NAP peptide) and a pharma- ceutical acceptable carrier, for use in treating or inhibiting the onset of a disease or disorder associated with abnormal functionality of Activity-Dependent Neuroprotective Protein (ADNP) in a gender-specific manner in a subject.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the disease or disorder is selected from a tauopathy, a neurodegenerative disease, a neurodevelopmental disease or a psychiatric disorder.

3. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the disease or disorder is selected from Progressive Supranuclear Palsy (PSP), schizophrenia, amnestic Mild Cognitive Impairment (aMCI), Alzheimer's disease, ADNP syndrome, autism and muscular diseases.

4. 4. The pharmaceutical composition for use according to claim 3, wherein the disease is progressive supranuclear palsy (PSP) and the use comprises treating or inhibiting the onset of PSP in a female subject.

5. 5. The pharmaceutical composition for use according to claim 4, wherein treating or preventing the onset of PSP comprises preventing or inhibiting an increase in ventricular size.

6. 6. The pharmaceutical composition for use according to any one of claims 4 to 5, wherein said treatment comprises improvement in at least one of the following symptoms associated with PSP: behavior, bulbar cranial nerve nucleus impairment, dysarthria, eye movement, limb movement and gait, improvement in parameters of the Schwab and England Activities of Daily Living Scale (SEADL), and / or parameters of the Geriatric Depression Rating Scale and Clinical Global Impression of Disease Severity.

7. The pharmaceutical composition for use according to any one of claims 4 to 6, wherein the female subject is 60 years of age or older.

8. The pharmaceutical composition for use according to any one of claims 4 to 7, wherein said pharmaceutical composition is administered intranasally.

9. The pharmaceutical composition for use according to any one of claims 4 to 8, wherein said use comprises administering said NAP peptide at 1 to 80 mg / day.

10. 10. The pharmaceutical composition for use according to claim 9, wherein said use comprises administering said NAP peptide at 40-80 mg / day.

11. 4. The pharmaceutical composition for use according to claim 3, wherein the disease is progressive supranuclear palsy (PSP) and the use comprises treating PSP in a male subject, the subject being administered 1-50 mg / day of the NAP peptide.

12. The pharmaceutical composition for use according to claim 11, wherein the male subject is 60 years of age or older.

13. 4. The pharmaceutical composition for use according to claim 3, wherein said disease is schizophrenia and said use comprises treating schizophrenia in a male subject, said use comprises administering to said subject 10-80 mg / day of said NAP peptide.

14. 4. The pharmaceutical composition for use according to claim 3, wherein said disease is schizophrenia and said use comprises treating schizophrenia in a female subject, said use comprises administering to said subject 1-4 mg / day of said NAP peptide.

15. 4. The pharmaceutical composition for use according to claim 3, wherein the disease is amnestic Mild Cognitive Impairment (aMCI) and the use comprises treating amnestic aMCI in a male subject, the use comprises administering to the subject 10-80 mg / day of the NAP peptide.

16. 4. The pharmaceutical composition for use according to claim 3, wherein the disease is amnesic mild cognitive impairment (aMCI) and the use comprises treating amnesic aMCI in a female subject, the use comprises administering to the subject 35-80 mg / day of the NAP peptide.

17. 4. The pharmaceutical composition of claim 3, wherein said use comprises the gender-specific treatment or prevention of Alzheimer's disease.

18. 18. The pharmaceutical composition for use according to claim 17, wherein the subject is in a prodromal stage of the disease.

19. 19. The pharmaceutical composition for use according to claim 17 or 18, wherein the Alzheimer's disease is characterized in that at least one of the following is present in a biological sample: (i) abnormal P53 protein, (ii) P-tau217, (iii) P-tau231, and (iii) P-tau181, and (iv) alterations in ADNP expression.

20. 20. A pharmaceutical composition for use according to any one of claims 17 to 19, comprising improving a parameter of the Geriatric Depression Rating Scale.

21. The pharmaceutical composition for use according to any one of claims 17 to 20, wherein said use comprises treating a female subject.

22. 22. The pharmaceutical composition for use according to claim 21, wherein said use comprises administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of said NAP peptide.

23. The pharmaceutical composition for use according to any one of claims 17 to 20, wherein said use comprises treating a male subject.

24. 24. The pharmaceutical composition for use according to claim 23, wherein said use comprises administering 1-80 mg / day, 1-10 mg / day, 20-40 mg / day, or 40-80 mg / day of said NAP.

25. The pharmaceutical composition for use according to any one of claims 1 to 24, wherein said use comprises intranasal administration of said pharmaceutical composition.

26. The pharmaceutical composition for use according to any one of claims 1 to 25, wherein said use comprises inhibiting neurodegeneration in said subject.

27. A pharmaceutical composition comprising a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1, NAP peptide) and a pharma- ceutical acceptable carrier, for use in ameliorating and / or preventing side effects of anti-amyloid beta therapy, wherein the therapy comprises an anti-amyloid beta antibody.

28. 28. The pharmaceutical composition for use according to claim 27, wherein said composition is administered in a gender-specific manner.

29. 29. The pharmaceutical composition for use according to claim 27 or 28, wherein the composition is administered to a female subject.

30. 30. The pharmaceutical composition for use according to claim 29, wherein said use comprises administering 1-70 mg / day, or 50-70 mg / day of said NAP peptide.

31. 29. The pharmaceutical composition for use according to claim 27 or 28, wherein the composition is administered to a male subject.

32. 32. The pharmaceutical composition for use according to claim 31, wherein said use comprises administering 1-70 mg / day, 1-50 mg / day, or 50-70 mg / day of said NAP.

33. The pharmaceutical composition for use according to any one of claims 27 to 32, wherein said use comprises administering said pharmaceutical composition at least one day before starting an anti-amyloid beta therapy.

34. The pharmaceutical composition for use according to any one of claims 27 to 33, wherein said use comprises administering said pharmaceutical composition in combination with said anti-amyloid beta therapy.

35. 35. The pharmaceutical composition for use according to any one of claims 27 to 34, wherein the anti-amyloid beta therapy comprises aducanumab or lecanemab.

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