Blarcamesine correction of EEG biomarkers in fragile x syndrome

Abstract

The present disclosure relates to Sigma-1 receptor agonists, and their target engagement and capacity to correct multiple EEG biomarkers of cortical dysfunction. The present disclosure further provides Precision Medicine or personalized therapy of using a Sigma-1 receptor agonist in treating neurodevelopmental and / or neurodegenerative disorder through engaging with EEG biological pathways. Also provided are kits for practicing the methods.

Description

Docket No: 085102-844842 PCT BLARCAMESINE CORRECTION OF EEG BIOMARKERS IN FRAGILE X SYNDROME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 641,259 filed May 1, 2024, and U.S. Provisional Patent Application Serial No. 63 / 668,894 filed July 9, 2024, each of which is entitled “BLARCAMESINE CORRECTION OF EEG BIOMARKERS IN FRAGILE X SYNDROME,” the disclosures of which are hereby incorporated by reference in their entirety. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to methods and kits of treating a neurodevelopmental or neurodegenerative disease in a subject by administering a Sigma-1 receptor agonist. Specifically, it is to deliver Precision Medicine or personalized therapy through monitoring changes in EEG and related biological pathways. BACKGROUND OF THE DISCLOSURE

[0003] Neurodevelopmental disorders or diseases refer to a group of conditions wherein the growth and development of the brain is affected, which in turn impact an individual’s ability in communications, emotions, behavior, self-control, learning, memory, cognition and / or critical thinking. Neurodevelopmental disorders include but not limited to Rett syndrome, Down's syndrome, William's Beuren syndrome, Prader- Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADFID, an anxiety disorder, Asperger's syndrome, an autistic disorder, depression, dyslexia, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, or Tourette's syndrome. These disorders currently have limited treatment options, thus demand for developing more therapeutics.

[0004] Fragile X syndrome (FXS), the most common inherited form of neurodevelopmental disability, is characterized by cognitive impairment, behavioral 1 103396107.1Docket No: 085102-844842 PCT abnormalities, and other dysfunctions linked to aberrant cortical processing. There is an urgent need for effective therapy against FXS. SUMMARY OF THE DISCLOSURE

[0005] One aspect of the present disclosure encompasses a method of treating a neurodevelopmental disorder with a Sigma-1 receptor agonist therapy in a subject in need thereof. The method comprises (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a treatment period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the treatment period; and (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non- medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. The method further comprises discontinuing the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG. When none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i). switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist.

[0006] Another aspect of the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3- yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); an enantiomer 2 103396107.1Docket No: 085102-844842 PCT thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, or any combination thereof. In yet another aspect, the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form (A2-73 freebase amorphous form); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine in crystal Form I (A2-73 Freebase Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in crystal Form II (A2-73 Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 Crystal Form III); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in amorphous form ((+) A2-73 amorphous form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form ((-) A2-73 amorphous form); (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in a crystal form ((+) A2-73 crystal form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((-) A2-73 crystal form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in amorphous form (A2-73 hydrogen fumarate amorphous form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I (A2-73 hydrogen fumarate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II (A2-73 hydrogen fumarate Crystal Form II); tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III (A2-73 hydrogen fumarate Crystal Form III); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in crystal Form IV (A2-73 hydrogen fumarate Crystal Form IV); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V (A2-73 hydrogen fumarate Crystal Form V); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I (A2-73 mesylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine sulfate in crystal Form I (A2-73 sulfate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II (A2-73 sulfate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine oxalate in crystal Form I (A2-73 oxalate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II 3 103396107.1Docket No: 085102-844842 PCT (A2-73 oxalate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine dihydrogen phosphate in crystal Form I (A2-73 dihydrogen phosphate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine edisylate in crystal Form I (A2-73 edisylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I (A2-73 benzoate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrobromide in crystal Form A (A2-73 hydrobromide Crystal Form A); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B (A2-73 hydrobromide Crystal Form B); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine maleate in crystal Form S5 (A2-73 maleate Crystal Form S5); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6 (A2-73 maleate Crystal Form S6); co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with tartaric acid (A2-73 co-crystal with tartaric acid Crystal Form CSII); co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with citric acid (A2-73 co-crystal with citric acid Crystal Form CSIII); co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with malic acid (A2-73 co-crystal with malic acid Crystal Form CSIV); a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride (A2-73 co-crystal with zinc chloride); a co-crystal of (-) tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((-) A2- 73 co-crystal with zinc chloride); a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((+) A2-73 co-crystal with zinc chloride); and any combination thereof. In another aspect, the Sigma-1 receptor agonist therapy comprises an oral composition comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof. In yet another aspect, the composition comprises about 5-50 mg of A2-73 free base or A2-73 Crystal Form I (for example, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg). In yet another aspect, the composition is for oral administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. In yet another aspect, the composition is for IV administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. 4 103396107.1Docket No: 085102-844842 PCT

[0007] Another aspect of the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 free base), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine hydrochloride (A19-144); and (1-(2, 8-dimethyl- l-thia-3, 8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); and any crystal form, any enantiomer, any pharmaceutically acceptable salt thereof, and any combination thereof. In one aspect, the Sigma-1 receptor agonist is A2-73. In another aspect, the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration. In yet another aspect, the treatment period is about 12 weeks or less. In yet another aspect, the treatment period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0008] Yet another aspect of the present disclosure encompasses the above method, and the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith- 5 103396107.1Docket No: 085102-844842 PCT Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli- Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome. In another aspect, the neurodevelopmental disease is Fragile X Syndrome. In yet another aspect, the subject is a pediatric, a teenager, or an adult human. In one aspect, the medial region comprises left medial region or right medial region. In another aspect, the non-medial region comprises a cortical region or a lobe region. In yet another aspect, the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof. In yet another aspect, the Test EEG or Control EEG comprises scalp EEG or intracranial EEG.

[0009] Yet another aspect of the present disclosure encompasses a method of selecting a Sigma-1 receptor agonist for treating a neurodevelopmental disorder in a subject in need thereof, the method comprising (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the subject for a trial period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the trial period; (c) selecting the Sigma-1 receptor agonist for the subject, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non- medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. In one aspect, the method further comprises discontinuing the Sigma-1 receptor agonist therapy for the subject when none of (i) –(iv) in (c) are observed on the Test EEG compared to the Control EEG. In yet another aspect, when none of (i) –(iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i) switching the subject to another Sigma-1 receptor agonist; (ii). switching the subject to another neurodevelopmental 6 103396107.1Docket No: 085102-844842 PCT drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist

[0010] Another aspect of the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3- yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, or any combination thereof. In yet another aspect, the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form (A2-73 freebase amorphous form); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine in crystal Form I (A2-73 Freebase Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in crystal Form II (A2-73 Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 Crystal Form III); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in amorphous form ((+) A2-73 amorphous form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form ((-) A2-73 amorphous form); (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in a crystal form ((+) A2-73 crystal form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((-) A2-73 crystal form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in amorphous form (A2-73 hydrogen fumarate amorphous form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I (A2-73 hydrogen fumarate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II (A2-73 hydrogen fumarate Crystal Form II); tetrahydro-N,N-dimethyl- 7 103396107.1Docket No: 085102-844842 PCT 2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III (A2-73 hydrogen fumarate Crystal Form III); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in crystal Form IV (A2-73 hydrogen fumarate Crystal Form IV); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V (A2-73 hydrogen fumarate Crystal Form V); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I (A2-73 mesylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine sulfate in crystal Form I (A2-73 sulfate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II (A2-73 sulfate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine oxalate in crystal Form I (A2-73 oxalate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II (A2-73 oxalate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine dihydrogen phosphate in crystal Form I (A2-73 dihydrogen phosphate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine edisylate in crystal Form I (A2-73 edisylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I (A2-73 benzoate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrobromide in crystal Form A (A2-73 hydrobromide Crystal Form A); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B (A2-73 hydrobromide Crystal Form B); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine maleate in crystal Form S5 (A2-73 maleate Crystal Form S5); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6 (A2-73 maleate Crystal Form S6); co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with tartaric acid (A2-73 co-crystal with tartaric acid Crystal Form CSII); co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with citric acid (A2-73 co-crystal with citric acid Crystal Form CSIII); co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with malic acid (A2-73 co-crystal with malic acid Crystal Form CSIV); a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride (A2-73 co-crystal with zinc chloride); a co-crystal of (-) tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((-) A2- 73 co-crystal with zinc chloride); a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2- 8 103396107.1Docket No: 085102-844842 PCT diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((+) A2-73 co-crystal with zinc chloride); and any combination thereof. In another aspect, the Sigma-1 receptor agonist therapy comprises an oral composition comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof. In yet another aspect, the composition comprises about 5-50 mg of A2-73 free base or A2-73 Crystal Form I (for example, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg). In yet another aspect, the composition is for oral administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. In yet another aspect, the composition is for IV administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg.

[0011] In one aspect, the Sigma-1 receptor agonist is selected from tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 free base), tetrahydro-N,N- dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); 1-(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); and (1-(2,8-dimethyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); and any crystal form, any enantiomer, any pharmaceutically acceptable salt thereof, and any combination thereof. In one aspect, the Sigma-1 receptor agonist is A2-73. In another aspect, the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration. In yet another aspect, the trial period is about 12 weeks or less. In yet another aspect, the trial period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In 9 103396107.1Docket No: 085102-844842 PCT yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for the trial period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0012] In yet another aspect, the present disclosure encompasses the above method, and the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith- Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli- Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome. In another aspect, the neurodevelopmental disease is Fragile X Syndrome. In yet another aspect, the subject is a pediatric, a teenager, or an adult human. In one aspect, the medial region comprises left medial region or right medial region. In another aspect, the non-medial region comprises a cortical region or a lobe region. In yet another aspect, the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof. In yet another aspect, the Test EEG or Control EEG comprises scalp EEG or intracranial EEG.

[0013] Another aspect of the present disclosure encompasses a method of using an encephalography (EEG) as an endpoint for a trial test of a Sigma-1 receptor agonist against a neurodevelopmental disorder in a trial subject, the method comprising (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the trial subject for a trial period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the trial subject before starting of the trial period; (c) identifying the trial subject as 10 103396107.1Docket No: 085102-844842 PCT meeting the trial endpoint, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. In another aspect, the method further comprises labeling the trial subject as failing to meet the surrogate endpoint when none of (i) –(iv) in (c) are observed on the Test EEG compared to the Control EEG. In yet another aspect, when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises (i) switching the trial subject to another Sigma-1 receptor agonist; (ii). switching the trial subject to another neurodevelopmental drug therapy; or (iii) switching the trial subject to a combination therapy comprising the Sigma-1 receptor agonist.

[0014] In another aspect, the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 free base), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine hydrochloride (A19-144); and (1-(2,8-dimethyl- l-thia- 3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); and any crystal form, any enantiomer, any pharmaceutically acceptable salt thereof, and any combination thereof. In one aspect, the Sigma-1 receptor agonist is A2-73. In another aspect, the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration. In yet another aspect, the trial period is about 12 weeks or less. In yet another aspect, the trial period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist 11 103396107.1Docket No: 085102-844842 PCT therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for the trial period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0015] In another aspect of the present disclosure encompasses the above method, and the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith- Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli- Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome. In another aspect, the neurodevelopmental disease is Fragile X Syndrome. In yet another aspect, the subject is a pediatric, a teenager, or an adult human. In one aspect, the medial region comprises left medial region or right medial region. In another aspect, the non-medial region comprises a cortical region or a lobe region. In yet another aspect, the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof. In yet another aspect, the Test EEG or Control EEG comprises scalp EEG or intracranial EEG.

[0016] Another aspect of the present disclosure encompasses a method of using a Sigma-1 receptor agonist in assessing a disease risk in a subject, the method comprising (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the subject for a test period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for 12 103396107.1Docket No: 085102-844842 PCT the subject before the start of the test period; (c) identifying the subject as at a risk for developing the disease, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. In one aspect, the disease is selected from the group consisting of Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio- facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome. In one aspect, the method further comprises assessing the subject having no current risk for the disease when none of (i) –(iv) in (c) are observed on the Test EEG compared to the Control EEG. In yet another aspect, when none of (i) –(iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises (i) recommending another diagnostic method to the subject; or (ii) starting a preventive therapy for the subject comprising the Sigma-1 receptor agonist.

[0017] Another aspect of the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3- yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, or any combination thereof. In yet another aspect, the Sigma-1 receptor 13 103396107.1Docket No: 085102-844842 PCT agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form (A2-73 freebase amorphous form); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine in crystal Form I (A2-73 Freebase Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in crystal Form II (A2-73 Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 Crystal Form III); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in amorphous form ((+) A2-73 amorphous form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form ((-) A2-73 amorphous form); (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in a crystal form ((+) A2-73 crystal form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((-) A2-73 crystal form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in amorphous form (A2-73 hydrogen fumarate amorphous form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I (A2-73 hydrogen fumarate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II (A2-73 hydrogen fumarate Crystal Form II); tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III (A2-73 hydrogen fumarate Crystal Form III); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in crystal Form IV (A2-73 hydrogen fumarate Crystal Form IV); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V (A2-73 hydrogen fumarate Crystal Form V); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I (A2-73 mesylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine sulfate in crystal Form I (A2-73 sulfate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II (A2-73 sulfate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine oxalate in crystal Form I (A2-73 oxalate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II (A2-73 oxalate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine dihydrogen phosphate in crystal Form I (A2-73 dihydrogen phosphate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- 14 103396107.1Docket No: 085102-844842 PCT furanmethanamine edisylate in crystal Form I (A2-73 edisylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I (A2-73 benzoate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrobromide in crystal Form A (A2-73 hydrobromide Crystal Form A); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B (A2-73 hydrobromide Crystal Form B); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine maleate in crystal Form S5 (A2-73 maleate Crystal Form S5); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6 (A2-73 maleate Crystal Form S6); co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with tartaric acid (A2-73 co-crystal with tartaric acid Crystal Form CSII); co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with citric acid (A2-73 co-crystal with citric acid Crystal Form CSIII); co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with malic acid (A2-73 co-crystal with malic acid Crystal Form CSIV); a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride (A2-73 co-crystal with zinc chloride); a co-crystal of (-) tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((-) A2- 73 co-crystal with zinc chloride); a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((+) A2-73 co-crystal with zinc chloride); and any combination thereof. In another aspect, the Sigma-1 receptor agonist therapy comprises an oral composition comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof. In yet another aspect, the composition comprises about 5-50 mg of A2-73 free base or A2-73 Crystal Form I (for example, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg). In yet another aspect, the composition is for oral administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. In yet another aspect, the composition is for IV administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg.

[0018] In one aspect, the Sigma-1 receptor agonist is selected from tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro- 15 103396107.1Docket No: 085102-844842 PCT N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 free base), tetrahydro-N,N- dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); 1-(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); and (1-(2, 8-dimethyl- l-thia-3, 8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); and any crystal form, any enantiomer, any pharmaceutically acceptable salt thereof, and any combination thereof. In one aspect, the Sigma-1 receptor agonist is A2-73. In another aspect, the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration. In yet another aspect, the test period is about 12 weeks or less. In yet another aspect, the test period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for the test period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0019] In one aspect, the present disclosure encompasses a method of treating a neurodevelopmental disease in a subject by administering a Sigma-1 receptor agonist, and such disease is Fragile X Syndrome. The method comprises (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a treatment period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography 16 103396107.1Docket No: 085102-844842 PCT (Control EEG), wherein the Control EEG was obtained for the subject before starting of the treatment period; and (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady- State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. The method further comprises discontinuing the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG. When none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i). switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist. In one aspect, the subject is a pediatric, a teenager, or an adult human. In yet another aspect, the medial region comprises left medial region or right medial region. In another aspect, the non-medial region comprises a cortical region or a lobe region. In yet another aspect, the non- medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof. In one aspect, the EEG comprises scalp EEG or intracranial EEG. In yet another aspect, the subject may have increased disease risk. In one aspect, assessing the disease risk comprises considering one or more factors of the subject selected from genetic profile, age, family history of the disease, use of tobacco products, being exposed to radiation, being exposed to a toxic chemical, being exposed to a virus, or being exposed to a bacterium.

[0020] Another aspect of the present disclosure encompasses the above method, and the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3- yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran- 17 103396107.1Docket No: 085102-844842 PCT 3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8- diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l-one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, or any combination thereof. In yet another aspect, the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form (A2-73 freebase amorphous form); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine in crystal Form I (A2-73 Freebase Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in crystal Form II (A2-73 Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III (A2-73 Crystal Form III); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in amorphous form ((+) A2-73 amorphous form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form ((-) A2-73 amorphous form); (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in a crystal form ((+) A2-73 crystal form); (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((-) A2-73 crystal form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in amorphous form (A2-73 hydrogen fumarate amorphous form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I (A2-73 hydrogen fumarate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II (A2-73 hydrogen fumarate Crystal Form II); tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III (A2-73 hydrogen fumarate Crystal Form III); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in crystal Form IV (A2-73 hydrogen fumarate Crystal Form IV); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V (A2-73 hydrogen fumarate Crystal Form V); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I (A2-73 mesylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine sulfate in crystal Form I (A2-73 sulfate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II (A2-73 sulfate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- 18 103396107.1Docket No: 085102-844842 PCT furanmethanamine oxalate in crystal Form I (A2-73 oxalate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II (A2-73 oxalate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine dihydrogen phosphate in crystal Form I (A2-73 dihydrogen phosphate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine edisylate in crystal Form I (A2-73 edisylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I (A2-73 benzoate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrobromide in crystal Form A (A2-73 hydrobromide Crystal Form A); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B (A2-73 hydrobromide Crystal Form B); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine maleate in crystal Form S5 (A2-73 maleate Crystal Form S5); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6 (A2-73 maleate Crystal Form S6); co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with tartaric acid (A2-73 co-crystal with tartaric acid Crystal Form CSII); co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with citric acid (A2-73 co-crystal with citric acid Crystal Form CSIII); co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with malic acid (A2-73 co-crystal with malic acid Crystal Form CSIV); a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride (A2-73 co-crystal with zinc chloride); a co-crystal of (-) tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((-) A2- 73 co-crystal with zinc chloride); a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride with zinc chloride ((+) A2-73 co-crystal with zinc chloride); and any combination thereof. In another aspect, the Sigma-1 receptor agonist therapy comprises an oral composition comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof. In yet another aspect, the composition comprises about 5-50 mg of A2-73 free base or A2-73 Crystal Form I (for example, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg). In yet another aspect, the composition is for oral administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. In yet another aspect, the composition is for IV 19 103396107.1Docket No: 085102-844842 PCT administration and comprises A2-73 in an amount of about 5 mg, about 10 mg, about 20 mg, or about 30 mg. REFERENCE TO COLOR FIGURES

[0021] The application file contains at least one drawing or photograph executed in color. Copies of publication of this patent application with color drawings or photographs will be provided by the Office upon request and payment of the necessary fee. BRIEF DESCRIPTION OF THE FIGURES

[0022] FIGS.1A to 1B depict the study design. FIG.1A depicts different brain regions. FIG.1B provides testing groups and testing procedures.

[0023] FIGS.2A to 2C depict reductions in EEG resting state power observed in various cortical regions under the treatment doses of 1 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. Ratio of Fmr1 KO post-treatment (black bars) to Fmr1 KO pre-treatment (white bars) represent EEG resting state power across frequency bands for distinct brain regions. Bars represent group means and error bars represent standard error of the mean (SEM). Statistical significance (*p < 0.05; ** p < 0.01; *** p < 0.001).

[0024] FIGS.3A to 3C depict improvements in chirp synchronization (ITPC) observed in various cortical regions under the treatment doses of 1 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. For each brain region, the left panel shows the averaged Fmr1 KO pre-treatment, the middle panel shows the averaged Fmr1 KO post-treatment, and the right panel shows Fmr1 KO post-treatment - Fmr1 KO pre-treatment. Significant increases in ITPC in Fmr1 KO post compared to Fmr1 KO pre mice are shown in black outlined areas.

[0025] FIGS.4A to 4C depict improvements in 40 Hz ASSR synchronization (ITPC) observed in all regions except for the left and right medial regions, under the treatment doses of 1 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. For each brain region, the left panel shows the averaged Fmr1 KO pre-treatment, the middle panel shows the averaged Fmr1 KO post-treatment, and the right panel shows Fmr1 KO post-treatment - Fmr1 KO pre-treatment. Significant increases in 20 103396107.1Docket No: 085102-844842 PCT ITPC in Fmr1 KO post compared to Fmr1 KO pre mice are shown in black outlined areas.

[0026] FIGS.5A to 5C depict improvements in 80 Hz ASSR synchronization (ITPC) observed in left and right medial regions, under the treatment doses of 1 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. For each brain region, the left panel shows the averaged Fmr1 KO pre-treatment, the middle panel shows the averaged Fmr1 KO post-treatment, and the right panel shows Fmr1 KO post- treatment - Fmr1 KO pre-treatment. Significant increases in ITPC in Fmr1 KO post compared to Fmr1 KO pre mice are shown in black outlined areas. DETAILED DESCRIPTION

[0027] The present disclosure is based in part on the discovery that Sigma-1 receptor agonist affects electroencephalographic (EEG) abnormalities, such as those related to neurodevelopmental diseases or disorders. The present disclosure further observes the Sigma-1 receptor agonist significantly improves EEG in resting power and network synchronization (inter-trial phase coherence, ITPC), a measure of cortical circuit synchronization, in a dose-dependent manner. These observations demonstrate target engagement of the Sigma-1 receptor agonist and its capacity to correct multiple EEG biomarkers related to cortical dysfunctions in various neurodevelopmental diseases or disorders. Such discovery supports multiple use aspects. For example, in one aspect, EEG normalization can be used as an indicator for treatment effects and / or to achieve personalized therapy by selecting a specific Sigma-1 receptor agonist for a specific patient through monitoring changes in EEG. Another aspect is to evaluate treatment efficiency and / or efficacy of the Sigma-1 receptor agonist. Yet another aspect, EEG changes are used as endpoints in a trial testing efficacy of a Sigma-1 receptor agonist against a neurodevelopmental disease(s) or disorder(s). Yet in another aspect, EEG changes can guide endpoint selection for a trial related to the Sigma-1 receptor agonist. Yet in another aspect, a subject’s EEG profile and / or its changes can be used to assess the subject’s disease state or risk. The present disclosure focuses on neurodevelopmental and / or neurodegenerative disorder treatment with Sigma-1 receptor agonist therapy. But the same principle and methods can be similarly applied to other classes of therapeutic agents and diseases. 21 103396107.1Docket No: 085102-844842 PCT

[0028] Sigma-1 receptors are involved in higher-ordered brain functions including memory, cognition, and critical thinking. Thus, a Sigma-1 receptor agonist therapy is often prescribed to subjects with memory or cognition impairment, such as those with neurodegenerative and / or neurodevelopmental disorders. The present disclosure provides that a Sigma-1 receptor agonist may correct or change a subject’s EEG abnormality. This corrected / changed EEG function reflects and / or effectuates improvements in memory and / or cognition in a subject having a neurodevelopmental disease or disorder. In one aspect, the corrected / changed EEG profile may be used as an indicator to evaluate the therapeutic effect and as a surrogate endpoint for clinical trials involving treating a neurodevelopmental disease or disorder. In another aspect, the corrected / changed EEG profile may be used to assess disease risk and / or monitor the effectiveness of a therapy against a specific patient, thus design a personalized therapy. In yet another aspect, the EEG profile can be used to determine if a subject is responsive to a Sigma-1 receptor agonist therapy. In yet another aspect, the Sigma-1 receptor agonist can be used a probe to see if a subject is having, or is suspected of having, or at a risk of having a disease linked to EEG abnormalities, such as Fragile X Syndrome (FXS), Rett Syndrome, Angelman Disease, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli- Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome. One exemplary Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride (ANAVEX® 2-73, or A2-73), its crystal forms, its enantiomer forms, its freebase, and / or salts of the freebase, as well as the crystal forms thereof. I. Electroencephalograph (EEG) and Biological Functions of the Brain

[0029] One aspect of the present disclosure relates to monitoring the impact of Sigma-1 receptor agonist on electroencephalograph (EEG). EEG is an electrogram record of spontaneous electrical activities of the brain. It can be obtained through non-invasive methods by placing EEG electrodes along the scalp (commonly called "scalp EEG"), or through "intracranial EEG", wherein electrodes are surgically placed 22 103396107.1Docket No: 085102-844842 PCT in the brain. The bio-signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex and allocortex, thus are used extensively in neurological research, such as in cognitive science, cognitive psychology, neurolinguistics, and psychophysiology. One specific measurement relates to EEG is event-related potential (ERP). It is obtained by measuring brain response to an external stimulus, such as stimulus’s impacts on a specific sensory, cognitive, or motor event. Together with EEG, ERP provides a noninvasive means of evaluating brain functions and responses. EEG and ERP have been used in research on mental disabilities, such as auditory processing disorder (APD), attention deficit disorder (ADD), or Attention-deficit / hyperactivity disorder (ADHD). They are also widely used in studying human functions such as swallowing or speech.

[0030] Another aspect of the present disclosure relates to electroencephalograph (EEG) and its signals collected from various parts of the brain. At a high level, the brain can be divided into three segments: the cerebrum, brainstem and cerebellum. The cerebrum (front of brain) comprises gray matter (the cerebral cortex) and white matter at its center. As the largest part of the brain, the cerebrum controls a broad range of activities and functions, such as initiating and coordinating movements and regulating body temperature. Other areas of the cerebrum enable speech, judgment, thinking and reasoning, problem-solving, emotions and learning. Other functions relate to vision, hearing, touch and other senses. Cerebral cortex refers to the outer gray matter covering of the cerebrum. The cortex has a large surface area due to its folds and comprises about half of the brain’s weight. The cerebral cortex is divided into two halves, or hemispheres. It is covered with ridges (gyri) and folds (sulci). The two halves join at a large, deep sulcus (the interhemispheric fissure, i.e., the medial longitudinal fissure) that runs from the front of the head to the back. The right hemisphere controls the left side of the body, and the left half controls the right side of the body. The two halves communicate with one another through a large, C- shaped structure of white matter and nerve pathways called the corpus callosum. The corpus callosum is in the center of the cerebrum. The neocortex is part of the human brain's cerebral cortex where higher cognitive functioning is thought to originate from. Due to the natural grooves and ridges in the brain, the neocortex is comprised of four main lobes with specific functions. The brainstem refers to the 23 103396107.1Docket No: 085102-844842 PCT middle of the brain, and it connects the cerebrum with the spinal cord. The brainstem includes the midbrain, the pons and the medulla. The midbrain (or mesencephalon) is a very complex structure with a range of different neuron clusters (nuclei and colliculi), neural pathways and other structures. These features facilitate various functions, from hearing and movement to calculating responses and environmental changes. The midbrain also contains the substantia nigra, an area affected by Parkinson’s disease that is rich in dopamine neurons and part of the basal ganglia, which enables movement and coordination. The pons is the origin for four of the 12 cranial nerves, which enable a range of activities such as tear production, chewing, blinking, focusing vision, balance, hearing and facial expression. The pons functions as a bridge and enables the connection between the midbrain and the medulla. The medulla is situated at the bottom of the brainstem; the medulla is where the brain meets the spinal cord. The medulla is essential to survival. Functions of the medulla regulate many bodily activities, including heart rhythm, breathing, blood flow, and oxygen and carbon dioxide levels. The medulla produces reflexive activities such as sneezing, vomiting, coughing, and swallowing. The spinal cord extends from the bottom of the medulla and through a large opening in the bottom of the skull. Supported by the vertebrae, the spinal cord carries messages to and from the brain and the rest of the body. Based on the location, the brain can be split as left and right hemisphere, and each brain hemisphere (parts of the cerebrum) has four sections or lobes: frontal, parietal, temporal and occipital. Each lobe controls specific functions. The frontal lobe is located in the front of the head and is the largest lobe of the brain. It is involved in personality characteristics, decision-making and movement. Recognition of smell usually involves parts of the frontal lobe. The frontal lobe contains Broca’s area, which is associated with speech ability. The parietal lobe is the middle part of the brain. It helps a person identify objects and understand spatial relationships (where one’s body is compared with objects around the person). The parietal lobe is also involved in interpreting pain and touch in the body. The parietal lobe houses Wernicke’s area, which helps the brain understand spoken language. The occipital lobe is at the back part of the brain that is involved with vision. Temporal lobes are at the sides of the brain and involved in short-term memory, speech, musical rhythm and some degree of smell recognition. Further, brain tissue is protected by meninges, which is a three-layer protective covering surrounding the brain and the spinal cord. The outermost layer, the dura mater, is 24 103396107.1Docket No: 085102-844842 PCT thick and tough. It includes two layers: the periosteal layer of the dura mater lines the inner dome of the skull (cranium) and the meningeal layer is below that. Spaces between the layers allow for the passage of veins and arteries that supply blood flow to the brain. The arachnoid mater is a thin, weblike layer of connective tissue that does not contain nerves or blood vessels. Below the arachnoid mater is the cerebrospinal fluid, or CSF. This fluid cushions the entire central nervous system (brain and spinal cord) and continually circulates around these structures to remove impurities. The pia mater is a thin membrane that hugs the surface of the brain and follows its contours. The pia mater is rich with veins and arteries. There are sophisticated and deep structures inside the brain, such as pituitary gland, hypothalamus, amygdala, hippocampus, pineal gland, and ventricles and cerebrospinal fluid. The pituitary gland, also called the “master gland,” is a pea-sized structure found deep in the brain behind the bridge of the nose. The pituitary gland governs the function of other glands in the body, regulating the flow of hormones from the thyroid, adrenals, ovaries, and testicles. It receives chemical signals from the hypothalamus through its stalk and blood supply. The hypothalamus is located above the pituitary gland and sends it chemical messages that control its function. It regulates body temperature, synchronizes sleep patterns, controls hunger and thirst and also plays a role in some aspects of memory and emotion. Amygdala refers to small, almond-shaped structures, located under each half (hemisphere) of the brain. It is included in the limbic system and regulates emotion and memory and is associated with the brain’s reward system, stress, and the “fight or flight” response when someone perceives a threat. Hippocampus is a curved seahorse-shaped organ on the underside of each temporal lobe, the hippocampus is part of a larger structure called the hippocampal formation. It supports memory, learning, navigation, and perception of space. It receives information from the cerebral cortex and may play a role in Alzheimer’s disease. Pineal gland is located deep in the brain and attached by a stalk to the top of the third ventricle. The pineal gland responds to light and dark and secretes melatonin, which regulates circadian rhythms and the sleep- wake cycle. Finally, ventricles and cerebrospinal fluid refer to four open areas deep in the brain with passageways between them. They also open into the central spinal canal and the area beneath arachnoid layer of the meninges. The ventricles manufacture cerebrospinal fluid, or CSF, a watery fluid that circulates in and around the ventricles and the spinal cord, and between the meninges. CSF surrounds and 25 103396107.1Docket No: 085102-844842 PCT cushions the spinal cord and brain, washes out waste and impurities, and delivers nutrients. As loosely used in the present disclosure, a medial region of the brain means the parts toward the middle or center. It is the opposite of lateral. Therefore, medial region comprises left medial region or right medial region. In contrast, non- medial region refers to the lateral part of the brain. It comprises a cortical region or a lobe region, such as neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe. The neocortex is part of the human brain's cerebral cortex where higher cognitive functioning is thought to originate from. Due to the natural grooves and ridges in the brain, the neocortex is comprised of four main lobes with specific functions. In the human brain, the neocortex takes up 90% of cerebral cortex. The allocortex, or heterogenetic cortex, is the other type of cerebral cortex in the brain, it takes up just 10% of the cerebral cortex in human brain. Allocortex is characterized by having just three or four cortical layers, in contrast with the six layers of the neocortex. There are three subtypes of allocortex: the paleocortex, the archicortex, and the periallocortex—a transitional zone between the neocortex and the allocortex.

[0031] Since the electrical activities monitored by EEG originates in neurons in the underlying brain tissue, the recordings made by the electrodes on the surface of the scalp vary in accordance with their orientation and distance to the source of the activity. Furthermore, the electrical activities recorded are distorted by intermediary tissues and bones. The above factors mean not all neurons will contribute equally to an EEG signal, with an EEG predominately reflecting the activity of cortical neurons. Deep structures within the brain further away from the electrodes will not contribute directly to an EEG; such as the base of the cortical gyrus, mesial walls of the major lobes, hippocampus, thalamus, and brain stem. EEG may detect signals both in medial and non-medial regions. Medial region comprises left medial region or right medial region. The non-medial region comprises a cortical region or a lobe region, such as neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe. A healthy human EEG will show certain patterns of activity that correlate with how awake a person is. The observed frequencies are subdivided into various groups: alpha (8–13 Hz), beta (13–30 Hz), delta (0.5–4 Hz), and theta (4–7 Hz). Alpha waves are observed when a person is in a state of relaxed wakefulness and are mostly prominent over the parietal and occipital sites. During intense mental activity, beta waves are more prominent in frontal areas as well as other regions. If a 26 103396107.1Docket No: 085102-844842 PCT relaxed person is told to open their eyes, one observes alpha activity decreasing and an increase in beta activity. Theta and delta waves are not seen in wakefulness, and if they are, it is a sign of brain dysfunction. Further, a diseased brain may show abnormal EEG as manifested by abnormal electrical discharges, such as sharp waves, spikes, or spike-and-wave complexes that are seen in people with epilepsy; thus, it is often used to inform and / or assist the medical diagnosis. EEG can detect the onset and spatio-temporal (location and time) evolution of seizures and the presence of status epilepticus. EEG has been found helpful in diagnosing various diseases, such as sleep disorders, coma, brain hemorrhage, encephalopathies, cerebral hypoxia after cardiac arrest, and brain death. EEG used to be a first-line method of diagnosis for tumors, stroke, and other focal brain disorders, but this use has decreased with the advent of high-resolution anatomical imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Despite its limited spatial resolution, EEG continues to be a valuable tool for research and diagnosis. It is one of the few mobile techniques available and offers millisecond-range temporal resolution, which is not possible with CT, PET, or MRI.

[0032] Another aspect of the present disclosure relates to identify and monitor treatment impact and / or efficacy of a Sigma-1 receptor agonist, such as ANAVEX®2- 73 (A2-73), against a neurodevelopmental disorder or a neurodegenerative disorder, such as Rett syndrome or Fragile X Syndrome. In one aspect, the treatment impact and / or efficacy is reflected by changes in EEG. In another aspect, the changes in EEG manifests treatment effect. In yet another aspect, the Sigma-1 agonist used is ANAVEX®2-73 (A2-73). In another aspect, these changes in EEG indicate a potential for using EEG as a parameter or indicator to design Precision Medicine for individual patients. In yet another aspect, the changes in EEG are associated with or correlated with efficacy or effectiveness of a Sigma-1 receptor agonist in treating various neurodegenerative disorders and / or neurodegenerative diseases and disorders. In one aspect, the neurodevelopmental or neurodegenerative diseases or disorders may include Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, Down's 27 103396107.1Docket No: 085102-844842 PCT syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X syndrome, ICF syndrome, Neurofibromatosis, Smith-Lemli-Opitz syndrome, an addictive disorder, ADD, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, or a combination thereof.

[0033] Another aspect of the present disclosure relates to use of changes in EEG as surrogate endpoints in trials, such as a drug interventional clinical trial. Often, therapeutic efficacy of a Sigma-1 receptor agonist is measured in the trial setting with physiological endpoints, such as physical parameters and / or cognitive behaviors indicative of the disorder in trial. These physiological endpoints are different for different disorders. For example, physiological endpoints for Alzheimer’s are different from those for Rett syndrome or Fragile X Syndrome. These endpoints measure both the pathology of each disease as well as the therapeutic response to the Sigma-1 receptor agonist, such as ANAVEX® 2-73. A surrogate biomarker for therapeutic response to Sigma-1 receptor agonist will simplify the design of clinical trials for each of these disorders, replacing the inherent analytical variability of the endpoint measurements for these diseases, as well as the length and size of these clinical trials. This surrogate endpoint may also be applicable across other clinical indications for Sigma-1 receptor agonist. The present disclosure presents an unexpected finding that changes in EEG or corrections of abnormal EEG may be used as a surrogate endpoint for therapeutic efficacy against various neurodevelopmental and / or neurodegenerative diseases and disorders. Such diseases or disorders may include Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett Syndrome, cerebral palsy, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD- NOS), childhood disintegrative disorder, Smith-Magenis syndrome, multiple sclerosis, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X syndrome, ICF syndrome, Neurofibromatosis, Smith-Lemli- Opitz syndrome, an addictive disorder, ADD, ADHD, an anxiety disorder, Asperger's 28 103396107.1Docket No: 085102-844842 PCT syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, or a combination thereof. II. Changes in EEG and Sigma-1 Receptor Agonist Therapy and Disease Treatment

[0034] The present disclosure relates to identify and monitor treatment impact and / or effect of a Sigma-1 receptor agonist, such as ANAVEX®2-73, against a neurodevelopmental disorder or a neurodegenerative disorder, such as Rett syndrome or Fragile X Syndrome. In one aspect, the treatment impact and / or effect is reflected by changes in EEG, such as corrections of abnormal EEG. Previous studies show that genes associated with neurodevelopmental disorders are often involved in brain development, neuronal signaling, or synaptic plasticity. So brain activities and its related biomarkers can be used to assess disease-relevant outcomes. Electroencephalography (EEG) is a noninvasive biomarker for brain functions and stimulations. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. Current studies include quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, and such quantitative analysis may quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes.

[0035] In one aspect, the method of treating a neurodevelopmental disorder with a Sigma-1 receptor agonist therapy in a subject in need thereof comprises (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a treatment period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the treatment period; and (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady- State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. The method 29 103396107.1Docket No: 085102-844842 PCT further comprises discontinuing the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG. When none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i). switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist.

[0036] Neurodevelopmental diseases refer to a group of conditions wherein the growth and development of the brain is affected, which in turn impact an individual's language, emotions, behavior, self-control, learning and memory. A sub-group is genetic neurodevelopmental diseases, indicating they may relate to abnormal or dysfunctions of genes, and may be hereditary. These disorders include, but not limited to, Rett Syndrome, Down's syndrome, William's Beuren syndrome, Prader- Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X-syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, depression, dyslexia, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, or Tourette's syndrome. Another class of neurodevelopmental disorders are complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction. They are considered to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but there are few confirmed associations.

[0037] Rett syndrome (RTT), originally termed cerebroatrophic hyperammonemia, is a rare genetic postnatal neurological disorder of the grey matter of the brain that almost exclusively affects females but has also been found in male patients. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and / or repeatedly putting hands into the mouth, are also noted. 30 103396107.1Docket No: 085102-844842 PCT People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and about 50% of affected individuals do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic. The signs and symptoms of Rett Syndrome are most easily confused with those of Angelman syndrome, cerebral palsy, and autism. Rett syndrome occurs in approximately 1:10,000 live female births in all geographies, and across all races and ethnicities. Without being bound by any particular theory, it is believed that Rett syndrome is caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA) and can arise sporadically or from germline mutations. Rett syndrome is initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene. The clinical progression of Rett syndrome has been well described and divided into 4 stages. In general, girls have relatively normal development in infancy with onset of regression after 6 months of age and deceleration of head growth. More than half of patients with Rett syndrome will develop epilepsy, and progressive motor and cognitive decline throughout childhood is common. Characteristic EEG patterns have emerged in Rett syndrome, although they are not necessarily specific to Rett syndrome. Early studies demonstrated that rhythmic slowing was the most common abnormality detected on EEG in Rett syndrome, followed by spike-wave complexes. In Rett syndrome, EEG progressed to ill-defined low-voltage recordings with age. This EEG deterioration was further categorized into stages from normal (stage 1) to poorly formed low voltage background (stage 4). Rhythmic theta in the central region has also been identified as a notable feature on EEG in patients with Rett syndrome and hypothesized to be indicative of impaired motor control due to frontal lobe dysfunction. Because of these patterns, EEG has been used as a powerful diagnostic tool in differentiating children with Rett and Angelman syndrome before genetic testing was clinically available. Studies on relationship between EEG abnormalities and pheno-type divides cases into the classic phenotype (most common), Hanefeld variant (rare severe), and preserved speech variant (PSV, rare mild) and accounted for severity of epilepsy (e.g., no epilepsy, epilepsy, or treatment- resistant epilepsy). In measures of network connectivity, Rett syndrome—MECP2 participants demonstrated a pattern of low covariance in left occipital-temporal pairs and reduced involvement of right occipital-temporal pairs. When comparing variable 31 103396107.1Docket No: 085102-844842 PCT phenotypes (e.g., classic vs Hanefeld vs preserved speech variant), there was no significant difference in EEG power or hemispheric variance, though there was a trend toward higher power in high-range frequencies in classic Rett syndrome and left hemisphere asymmetry in Hanefeld and preserved speech variant (PSV) Rett syndrome. There was a significant difference in network connectivity between the phenotypes where the classic and preserved speech variant groups had an overall pattern of low network activity in bioccipital regions and the Hanefeld group had low covariance in the delta band. Clinical EEG abnormalities are found to correlate with clinical severity and progression of Rett disease. It is noted that months after the initial EEG, there is a decrease in spectral power that was most notable in the left frontal and parietal regions. When comparing rgw severity of epilepsy, there was no difference in overall spectral power or among individual frequency bands between the 3 groups, but there was a pattern of increasing left occipital predominance with increasing severity of epilepsy and differences in overall network architecture. Finally, it is demonstrated that an increased power in the low-frequency bands (e.g., delta and theta) in the post-regression phase correlates to lower scores on standardized cognitive assessment measures. In one aspect, the present disclosure uses EEG as a translational biomarker, indicating severity of Rett syndrome and / or therapeutic efficacy of an interventional drug administration.

[0038] Fragile X Syndrome (FXS), also known as Martin-Bell syndrome, is a rare non-Mendelian trinucleotide repeat disorder. There are fewer than 200,000 US cases per year. FXS is the most prevalent inherited cause of mild-to-severe intellectual disability and the most common monogenic cause of autism spectrum disorder. It accounts for about one-half of cases of X-linked intellectual disability and is the most common cause of mental impairment after trisomy 21. Trinucleotide repeat expansions result in silencing of expression of the FMR1 gene on the X chromosome causing fragile X syndrome (FXS), the most prevalent monogenetic causes of global developmental delay and autism spectrum disorder. Decreased or absent fragile X messenger ribonucleoprotein (FMRP), the protein product of FMR1, leads to abnormal dendritic pruning, an increased number of dendrites in addition to increased dendritic length, and abnormal synaptic plasticity. Most patients with fragile X syndrome (full mutation with >200 CGG repeats) are male. Many clinical trials of treatments that target the underlying pathology of Fragile X Syndrome have been 32 103396107.1Docket No: 085102-844842 PCT evaluated in clinical trial, but none have demonstrated sufficient benefit to be approved. Further, Fragile X syndrome (FXS) is a candidate disorder for viral- mediated gene transfer therapy and preclinical studies demonstrated rescue of social deficits and abnormal slow-wave activity on EEG in male Fmrl-knockout rats treated with AAV9-FMR1. Among individuals with FXS, retrospective studies of EEGs obtained for a clinical suspicion of seizures demonstrated back-ground slowing and epileptiform discharges. About a third of FXS children have features of autism and delayed speech that are present from an early age. FXS is underdiagnosed, leading to suboptimal management and patient outcomes. Occurrence wise, FXS with a full mutation allele occurs in approximately 1 in 7000 males and 1 in 11,000 females; however, the exact frequency is unknown. Female carrier status is estimated to be as high as 1 in 130 to 250 individuals, and the incidence of male carriers is about 1 in 250 to 800 individuals. However, it is essential to note that the carrier frequency can vary greatly based on the diagnostic testing used and the population of interest. Treatment wise, there is no cure for the disease, but medications can be used for symptom-based relief to minimize behavioral and mental health challenges associated with FXS. For example, stimulants may target FXS hyperactivity, impulsivity, and attention issues. Antidepressants (e.g., bupropion, buspirone, or selective serotonin and norepinephrine reuptake inhibitors) may treat anxiety, obsessive-compulsive behaviors, and mood disorders in FXS patients.

[0039] In FXS patients, resting state EEG with eyes closed has shown increased theta power and reduced alpha power, suggestive of an imbalance of excitatory and inhibitory cortical circuit activity. Studies on neural architecture of anatomical and functional connectivity across brain regions suggest immature cortical networks. In typical development, synaptic growth and pruning are associated with decreasing delta and theta power coupled with increasing long-range alpha and beta density. In FXS patients, the opposite was seen with a decrease in functional connectivity within alpha and beta frequency bands and increased connectivity within theta frequency bands. Further, increased path length in theta bands is found when comparing to healthy controls. These findings support the theory of impaired cortical maturation in FXS disorder. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of a Sigma-1 agonist therapy. 33 103396107.1Docket No: 085102-844842 PCT

[0040] Angelman syndrome is a genetic disorder causing developmental disabilities and nerve-related symptoms. It typically cannot be detected until developmental delays become noticeable, usually when a baby is about six to 12 months old. Symptoms may include lack of crawling or babbling, minimal speech, and frequent smiling and laughter. Inability to walk, move, or balance well (ataxia) is also a symptom. Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity and a short attention span are common. Most affected children also have difficulty sleeping and need less sleep than usual. With age, people with Angelman syndrome become less excitable, and the sleeping problems tend to improve. However, affected individuals continue to have intellectual disability, severe speech impairment, and seizures throughout their lives. Adults with Angelman syndrome have distinctive facial features that may be described as "coarse." Other common features include unusually fair skin with light-colored hair and an abnormal side-to-side curvature of the spine (scoliosis). The life expectancy of people with this condition appears to be nearly normal. Current treatment includes anti-seizure medication and therapies to help manage medical and developmental concerns. There is no approved drug therapy to directly target the impacted genes or malfunctioned neurons related to this disorder. Significant improvement in fine motor skills may correlate with a reduction in delta power in the ketone formulation treatment. It is considered that increased delta activity is a marker of neuronal dysfunction and disrupted connectivity, which is not being specific to Angelman syndrome. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against Angelman syndrome.

[0041] Huntington’s disease is a familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive chorea and dementia in the fourth or fifth decade of life. Common initial manifestations include paranoia, poor impulse control, depression, hallucinations, and delusions. Late symptoms include intellectual impairment, loss of fine motor control, athetosis, and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. Its juvenile variant has a more fulminant course including seizures, ataxia, dementia, and chorea. Amyotrophic lateral sclerosis is a 34 103396107.1Docket No: 085102-844842 PCT degenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous astrocytes and atrophy of anterior spinal nerve roots and corticospinal tracts. Prion disease is a group of genetic, infectious, or sporadic degenerative human and animal nervous system disorders associated with abnormal prions. These diseases are characterized by conversion of the normal prion protein to an abnormal configuration via a post-translational process. In humans, these conditions generally feature dementia, ataxia, and a fatal outcome. Pathologic features include a spongiform encephalopathy without evidence of inflammation. Some older literature may occasionally refer to these as unconventional slow virus diseases. In one aspect of the present disclosure, correction of EEG abnormalities in Huntington’s patients may correlate with therapeutic effects of a Sigma-1 agonist therapy.

[0042] Prion disease, also called “transmissible spongiform encephalopathies”both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. The causative agents of TSEs are believed to be prions. The term “prions” refers to abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain. The abnormal folding of the prion proteins leads to brain damage and the characteristic signs and symptoms of the disease. Prion diseases are usually rapidly progressive and always fatal. Human Prion disease comprises at least Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler- Scheinker Syndrome, Fatal Familial Insomnia, and Kuru. Animal Prion disease comprises at least Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Scrapie, Transmissible mink encephalopathy, Feline spongiform encephalopathy, and Ungulate spongiform encephalopathy. In one aspect of the 35 103396107.1Docket No: 085102-844842 PCT present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against Prion diseases.

[0043] Amyotrophic lateral sclerosis, or “ALS”, often also called Lou Gehrig's disease (after the baseball player who was diagnosed with it). It is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Its impact often starts in the hands, feet, or limbs, and then spreads to other parts of your body. As the disease advances and nerve cells are destroyed, your muscles get weaker. This eventually affects chewing, swallowing, speaking and breathing. Symptoms include, but not limited to, difficulty walking or doing normal daily activities, tripping, and falling, weakness in your legs, feet or ankles, hand weakness or clumsiness, slurred speech or trouble swallowing, muscle cramps and twitching in your arms, shoulders and tongue, inappropriate crying, laughing or yawning, and cognitive and behavioral changes. There is no cure for this fatal disease. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against ALS.

[0044] Cerebral palsy (CP) is a group of congenital disorders that affect a person's ability to move and maintain balance and posture. Cerebral palsy is due to abnormal brain development, often before birth, and may be related infection, blood clots, prematurity, genetic problems, or lack of oxygen in the brain. Symptoms include exaggerated reflexes, floppy or rigid limbs, and involuntary motions. These symptoms often appear by early childhood and is the most common motor disability in childhood. There is no cure for cerebral palsy, but supportive treatments, medications, and surgery can help many individuals improve their motor skills and communication abilities. Long-term treatment includes physical and other therapies, drugs, and sometimes surgery. A newly developed therapy called “Non-Invasive Brain Stimulation”, which involves a small electrical current being sent to the brain to stimulate specific areas. The aim of this therapy for cerebral palsy is to help improve movement and coordination by stimulating the part of the brain responsible for controlling these functions CP. A2-73 is being investigated to treat CP or relieve some of its symptoms. In one aspect of the present disclosure, correction of EEG 36 103396107.1Docket No: 085102-844842 PCT abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against CP.

[0045] Multiple sclerosis (MS) is a long-lasting (chronic) disease of the central nervous system. It is thought to be an autoimmune disorder, a condition in which the body attacks itself by mistake. MS is not considered as a genetic disorder, but genetic factors may play a role in the disease onset, development and progression. MS is an unpredictable disease that affects people differently. Some people with MS may have only mild symptoms. Others may lose their ability to see clearly, write, speak, or walk when communication between the brain and other parts of the body becomes disrupted. Myelin is the fatty tissue that surrounds and protects nerve fibers. In MS, the myelin is destroyed in many areas. This loss of myelin forms scar tissue called sclerosis. These areas are also called plaques or lesions. When the nerves are damaged in this way, they can’t conduct electrical impulses to and from the brain. About 50% of all people with MS have thinking (cognitive) problems linked to the disease. The effects of these problems may be mild. There is no cure yet for MS. But things can be done to help change the course of the disease, treat flare-ups, manage symptoms, and improve your function and mobility. A2-73 is being investigated to treat MS, and / or relieve its symptoms. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against MS.

[0046] Williams syndrome (WS) is an autosomal dominant disorder. Most individuals diagnosed with WS have the disorder as the result of a de novo 1.5- to 1.8-Mb 7q11.23 deletion; rarely, an individual with WS has an affected parent. Recommendations for the parents of a proband with WS include obtaining a medical history to determine if signs or symptoms of WS are present. In the absence of clinical findings of WS in the parents, testing of the parents for the 7q11.23 deletion identified in the proband is not warranted. Each child of an individual with WS has a 50% chance of inheriting the 7q11.23 deletion and being affected. Once the WS- causing 1.5- to 1.8-Mb 7q11.23 deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. The diagnosis can be directly established by identification of a heterozygous 1.5- to 1.8-Mb deletion of the Williams-Beuren syndrome critical region (WBSCR) on chromosome 7q11.23. 37 103396107.1Docket No: 085102-844842 PCT Clinical manifestation of WS include cardiovascular disease (elastin arteriopathy, most often manifesting as supravalvar aortic stenosis), developmental delay, usually mild intellectual disability, a specific cognitive profile, unique personality characteristics, connective tissue abnormalities, growth abnormalities, other endocrine manifestations, and distinctive facies. Additional manifestations can include sleep problems, ocular issues, hearing loss, dental problems, gastrointestinal difficulties, urinary tract abnormalities, and musculoskeletal issues. Currently treatments are limited to tackle each manifested disorders or symptoms. A2-73 is being investigated to treat Williams Syndrome, and / or relieve multiple symptoms thereof. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against Williams Syndrome.

[0047] Smith-Magenis syndrome (SMS) is a genetic disorder caused by a heterozygous deletion of or a heterozygous pathogenic variant in RAI1 on chromosome 17p11.2. The majority of 17p11.2 deletions are de novo, while deleterious variants in RAI1 can be de novo or inherited. Complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS occur but are rare. Although SMS usually occurs as the result of a de novo deletion of 17p11.2, rare instances of vertical transmission from an affected parent to a child, parental germline mosaicism, and complex familial chromosome rearrangements leading to del(17)(p11.2) and SMS have been reported. If the SMS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells. SMS is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and childhood- onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally 38 103396107.1Docket No: 085102-844842 PCT not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and / or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS. Currently treatments are limited to tackle manifested disorders or symptoms. A2-73 is being investigated to treat SMS, and / or relieve multiple symptoms or disordered related thereof. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against SMS.

[0048] Pervasive developmental disorders (PDD), also known as autism spectrum disorder (ASD), are neurological and developmental disorders that affect how people interact with others, communicate, learn, and behave. The term “pervasive developmental disorders” (PDD) used herein includes autism, Asperger's syndrome, childhood disintegrative disorder and an unspecified form of pervasive developmental disorder. It also includes "Asperger's syndrome," which is generally thought to be at the mild end of autism spectrum disorder. These disorders and diseases are the developmental disability caused by differences in the brain. People with PDD or ASD often have problems with social communication and interaction, and restricted or repetitive behaviors or interests. PDD or ASD can be characterized by delays in the development of social and communication skills. Parents may note symptoms as early as infancy, although the typical age of onset is by 3 years of age. Symptoms of PDD or ASD vary widely. Some children do not speak at all, while others speak in limited phrases or conversations, and some have relatively average language development. Repetitive play skills and limited social skills are generally evident. Extreme responses to sensory information, such as loud noises and lights, 39 103396107.1Docket No: 085102-844842 PCT are also common. Currently, there is no known cure for PDD. Medications may be used to address specific behavioral problems, and therapy should be specialized according to the needs of each child. Some children with PDD benefit from specialized classrooms and others function well in standard special education classes or regular classes with additional support. A2-73 is being investigated to treat PDD / ASD, and / or improve their social and communication skills thereof. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against PDD / ASD.

[0049] Childhood disintegrative disorder (CDD), also known as Heller's syndrome and disintegrative psychosis, is a rare condition characterized by late onset (>3 years of age) of developmental delays in language, social function, and motor skills. It is a complex disorder that affects many different areas of the child's development. It is grouped with pervasive developmental disorders (PDDs) and is related to the better known and more common disorder of autism. The cause of childhood disintegrative disorder is unknown. Research findings suggest, however, that it may arise in the neurobiology of the brain. About half the children diagnosed with CDD have an abnormal electroencephalogram (EEG). EEGs measure the electrical activity in the brain generated by nerve transmission (brain waves). CDD is also sometimes associated with seizures, as another indication that the neurobiology of the brain may be involved. Children with CDD have at least 2 years of normal development in all areas—language understanding, speech, skill in the use of large and small muscles, and social development. After this period of normal growth, the child begins to lose the skills he or she has acquired. This loss usually takes place between ages 3 and 4, but it can happen any time up to age ten. The prevalence of CDD is 1 in 100,000 boys and the ratio of boys to girls is estimated to be 8 boys to 1 girl. Currently treatments are limited to tackle manifested disorders or symptoms. A2- 73 is being investigated to treat CDD, and / or relieve multiple symptoms or disordered related thereof. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against CDD.

[0050] ADD and ADHD are both brain function disorders. They are one of the most common neurodevelopmental disorders of childhood, but their cause(s) and 40 103396107.1Docket No: 085102-844842 PCT risk factors are still unclear. Recent studies link genetic factors with ADHD. There is no single test to diagnose ADD or ADHD, because many other problems, like anxiety, depression, sleep problems, and certain types of learning disabilities, can have similar symptoms. Diagnosing ADHD usually includes a checklist for rating ADHD symptoms and taking a history of the child’s behavior. Symptoms include inattention, disorganization, constant daydreaming, impulsivity, hyperactivity, squirming, fidgeting, tapping, talking, and constant movement. Research shows that the brains of people with ADHD are different than those without. That is why some doctors use physical tests to look for changes in brain patterns. The FDA approved the use of electroencephalogram (EEG) to diagnose ADHD in 2013, called the Neuropsychiatric EEG-Based Assessment Aid (NEBA) System. This noninvasive scan measures slow brain waves called theta waves and fast brain waves called beta waves. NEBA records the number of slow and fast brain waves given off and calculates the ratio between the two. It is believed that the ratio is higher in people with ADHD. In one aspect of the present disclosure, correction of EEG abnormalities correlates with therapeutic effects of Sigma-1 agonist therapy against ADHD.

[0051] Other diseases or disorders encompassed by the present disclosure include, but not limited to, a disorder or condition related to neuron generations, neuron regenerations, and / or neuron communications to the nervous system.

[0052] Yet another aspect of the present disclosure encompasses a method of assessing a disease risk in a subject by monitoring EEG changes resulting from administration of a Sigma-1 receptor agonist. The disease comprises a neurodevelopmental or neurodegenerative disease or disorder, such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X- syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli-Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, ADD, Attention- 41 103396107.1Docket No: 085102-844842 PCT deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof. The method comprises the steps of (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a treatment period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the treatment period; and (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non- medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. The method further comprises discontinuing the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG. When none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i). switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist.

[0053] Yet another aspect of the present disclosure encompasses a method of using EEG changes or corrections as a surrogate endpoint for a trial in testing a Sigma-1 receptor agonist therapy. The method comprises the steps (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of the trial period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the trial period; and (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a 42 103396107.1Docket No: 085102-844842 PCT brain medial region. The method further comprises discontinuing the trial period with the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG. When none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of (i). switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist. The trial is for treating a neurodevelopmental or neurodegenerative disease or disorder, such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli- Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, ADD, Attention-deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof.

[0054] In any of the methods described herein, the subject may be a human subject. In another aspect, the subject may have or is suspected of having or have a risk of having a disorder or disease. In one aspect, such disease or disorder comprises Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X- syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli- Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, Attention-Deficit Disorder (ADD), Attention-deficit / hyperactivity disorder 43 103396107.1Docket No: 085102-844842 PCT (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof.

[0055] In various aspects, if a Sigma-1 receptor agonist therapy is identified as ineffective or rejected for a subject, a follow-up action may be taken. In another aspect, the follow-up action may comprise one or more of steps comprising switching the subject to another Sigma-1 receptor agonist, supplementing the subject with another therapy, adjusting doses or dose regimen of the Sigma-1 receptor agonist, or switching to a combined neurodegenerative or neurodevelopmental therapy.

[0056] The neurodevelopment or neurodevelopmental therapy comprises a Sigma-1 receptor agonist therapy, or a NMDA therapy, or a cognition enhancing physical therapy. For example, a neurodegenerative or neurodevelopmental therapy may comprise a drug therapy comprising a Sigma-1 receptor agonist, such as ANAVEX®2-73 (A2-73), ANAVEX®19-144 (A19-144), ANAVEX®1-41 (A1-41), AV1066, ANAVEX®3-71 (A3-71), PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L- 687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof. III. Sigma-1 Receptor Agonist

[0057] Sigma-1 receptors are involved in higher-ordered brain functions including memory and cognition. Thus, a Sigma-1 receptor agonist therapy is often prescribed to patients with memory or cognition impairment, such as those with neurodegenerative disorders. It has been discovered that following treatment with a Sigma-1 receptor agonist, a subject’s gene expression profiles are altered: a set of selected genes are differentially expressed, and their relevant gene clusters are overrepresented. The altered genetic profile can thus be used as a benchmark to evaluate the therapeutic effect of another therapeutic agent. It can also be used to select a Sigma-1 receptor agonist for a subject. Further, it can also be used to determine if a subject is responsive to a Sigma-1 receptor agonist therapy. Finally, the Sigma-1 receptor agonist can be used a probe to see if a subject is having, or is suspected of having, or at an increased risk of having, a disease linked to the altered gene expression profiles. 44 103396107.1Docket No: 085102-844842 PCT

[0058] In one aspect, the Sigma-1 receptor agonist is selected from the following. ANAVEX® 2-73 (A2-73) has the chemical name of tetrahydro-N, N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride. A2-73 free base has the chemical name of tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine. ANAVEX®19- 144 (A19-144) has the chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)-N- methylmethanamine hydrochloride. ANAVEX®1-41 (A1-41) has the chemical name of tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride. AV1066 has the chemical name of 1-(3-4(((1R,3S,5S)-adamantan-1-yl) (pheny)methyl) propyl)-4-methylpiperazine. ANAVEX®3-71 (A3-71, AF-710B) has a chemical name of 1-(2,8-dimethyl-1-thia-3,8-diazaspiro 4.5 decan-3-yl)-3-(1H-indol-3-yl) propan-1- one). The Sigma-1 receptor agonist can be any crystal form, any enantiomer, any pharmaceutically acceptable salt of the above compounds, and any combination thereof.

[0059] In various aspects, the Sigma-1 receptor agonist comprises tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form (A2-73 freebase amorphous form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I (A2-73 freebase Crystal Form I); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in crystal Form I (A2-73 Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II (A2-73 Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride in crystal Form III (A2-73 Crystal Form III); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form ((+) A2-73 amorphous form); (-) tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine hydrochloride in amorphous form ((-) A2-73 amorphous form); (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((+) A2-73 crystal form); (-) tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form ((-) A2-73 crystal form); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form (A2-73 hydrogen fumarate amorphous form); tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I (A2- 73 hydrogen fumarate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrogen fumarate in crystal Form II (A2-73 hydrogen fumarate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine 45 103396107.1Docket No: 085102-844842 PCT hydrogen fumarate in crystal Form III (A2-73 hydrogen fumarate Crystal Form III); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV (A2-73 hydrogen fumarate Crystal Form IV); tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V (A2-73 hydrogen fumarate Crystal Form V); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine mesylate in crystal Form I (A2-73 mesylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I (A2-73 sulfate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine sulfate in crystal Form II (A2-73 sulfate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I (A2-73 oxalate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine oxalate in crystal Form II (A2-73 oxalate Crystal Form II); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I (A2-73 dihydrogen phosphate Crystal Form I); tetrahydro-N,N- dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I (A2-73 edisylate Crystal Form I); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I (A2-73 benzoate Crystal Form I); tetrahydro-N,N-dimethyl- 2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A (A2-73 hydrobromide Crystal Form A); tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrobromide in crystal Form B (A2-73 hydrobromide Crystal Form B); tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5 (A2-73 maleate Crystal Form S5); tetrahydro-N,N-dimethyl-2,2- diphenyl-3-furanmethanamine maleate in crystal Form S6 (A2-73 maleate Crystal Form S6); co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid (A2-73 co-crystal with tartaric acid Crystal Form CSII); co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid (A2-73 co-crystal with citric acid Crystal Form CSIII); co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl- 3-furanmethanamine hydrochloride with malic acid (A2-73 co-crystal with malic acid Crystal Form CSIV); a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with zinc chloride (A2-73 co-crystal with zinc chloride); a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with zinc chloride ((-) A2-73 co-crystal with zinc chloride); a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3- 46 103396107.1Docket No: 085102-844842 PCT furanmethanamine hydrochloride with zinc chloride ((+) A2-73 co-crystal with zinc chloride); or any combination thereof.

[0060] In one aspect, the Sigma-1 receptor agonist is A2-73. In another aspect, the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration. In yet another aspect, the treatment period is about 12 weeks or less. In yet another aspect, the treatment period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg

[0061] ANAVEX® 2-73 (A2-73, blarcamesine) is a small molecule of Sigma-1 receptor agonist which binds to the SIGMAR1 receptor on the cell membrane. A2-73 has been tested for therapeutic clinical efficacy in various neurodegenerative and / or neurodevelopmental disorders, such as Alzheimer’s Disease, Parkinson’s Disease, Rett syndrome, Angelman syndrome, Williams syndrome, Fragile X Syndrome, among others. It has demonstrated encouraging therapeutic efficacy for patients with these neurological diseases. 47 103396107.1Docket No: 085102-844842 PCT

[0062] In one aspect, the Sigma-1 receptor agonist comprises A2-73 freebase in amorphous form, A2-73 freebase in crystal Form I, A2-73 in amorphous form, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-) A2-73 enantiomer. The A2-73 freebase in crystal Form I is disclosed and characterized in WO 2019 / 200345. Specifically, the A2-73 Freebase in crystal Form I is characterized substantially by XRPD pattern shown in FIG.16 of WO 2019 / 200345 and particle shapes depicted in FIG.15 of WO 2019 / 200345. In one aspect, A2-73 crystal is the Form I, Form II, and / or Form III crystals as disclosed and characterized in WO 2017 / 013498. Specifically, the A2-73 crystal Form I is characterized substantially by XRPD pattern shown in FIG.1 of WO 2017 / 013498 and particle shapes depicted in FIGs.2 and 3 of WO 2017 / 013498. The A2-73 crystal Form II is characterized substantially by XRPD pattern shown in FIG.4, particle shapes depicted in FIG.7 of WO 2017 / 013498, and the FTIR spectrum shown in FIG.5 of WO 2017 / 013498. The A2-73 crystal Form III is characterized substantially by XRPD pattern shown in FIG.8, particle shapes depicted in FIG.11 of WO 2017 / 013498, and the FTIR spectrum shown in FIG.9 of WO 2017 / 013498. The analog of A2-73 may include A1-41. The metabolite of A2-73 may include A19-144. In one aspect, the pharmaceutically acceptable salt comprises a hydrochloride salt, a hydrobromide salt, a fumarate salt, a sulfate salt, a dihydrogen phosphate salt, a benzoate salt, a mesylate salt, an edysilate salt, or an oxalate salt. In another aspect, the co-crystal comprises a A2-73 pharmaceutically acceptable salt with an organic acid comprising tartaric acid, citric acid, maleic acid, or a combination thereof. In another aspect, the A2-73 is A2-73 amorphous form, A2-73 Freebase crystal Form I, A2-73 crystal Form I, A2-73 crystal Form II, A2-73 crystal Form III, (+)A2-73 enantiomer, (-)A2-73 enantiomer. In one aspect, the active is A2-73 freebase fumarate salt and / or its crystals, such as A2-73 Freebase fumarate salt in amorphous form, A2-73 Freebase hydrogen fumarate salt crystal Form I, A2-73 Freebase hydrogen fumarate salt crystal Form II, A2-73 Freebase hydrogen fumarate salt crystal Form III, A2-73 Freebase hydrogen fumarate salt crystal Form IV, A2-73 Freebase hydrogen fumarate salt crystal Form V, all of which are disclosed and characterized in WO 2019 / 200345, such as XRPD patterns shown in FIG.29, FIG.30, FIG.32 FIG.33, and FIG.34, respectively. In another aspect, the A2-73 is other salt crystals, such as A2-73 Freebase Mesylate Form I, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Oxalate Form I, A2- 48 103396107.1Docket No: 085102-844842 PCT 73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Dihydrogen phosphate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase Benzoate Form I, all of which are disclosed and characterized in WO 2019 / 200345, such as XRPD patterns shown in FIGs.18-23 and 25-27, respectively. In yet another aspect, the active is A2-73 Freebase hydrobromide crystal Form A, A2-73 Freebase hydrobromide crystal Form B, A2-73 maleate crystal Form S5, or A2-73 maleate crystal Form S6. They are disclosed and characterized in WO 2021 / 158586. In yet another aspect, the active is co-crystal Form CSII of A2-73 co-crystal with tartaric acid, co-crystal Form CSIII of A2-73 co-crystal with citric acid, or co-crystal Form CSIV of A2-73 co-crystal with malic acid, which are disclosed and characterized in WO 2023 / 208133. In yet another aspect, the active is co-crystal of A2-73 with zinc chloride disclosed in U.S. Patent No.12,018,005. The full disclosures of each of WO 2017 / 013498; WO 2019 / 200345; WO 2021 / 158586; WO 2023 / 208133; and U.S. Patent No.12,018,005 are hereby incorporated by reference herein in their entirety.

[0063] In various aspects of the methods in the present disclosure, a Sigma-1 receptor agonist therapy comprises a A2-73 drug therapy by administering A2-73 freebase, a crystal form of A2-73 freebase, a salt of A2-73 freebase, a crystal form of A2-73 freebase salt, A2-73 amorphous form, a crystal form of A2-73 (blarcamesine), an enantiomer or stereoisomer of A2-73, a co-crystal of A2-73, an enantiomer or stereoisomer of A2-73 freebase, an enantiomer or stereoisomer of A2-73 freebase salt.

[0064] In another aspect, the Sigma-1 agonist is in a crystal form selected from A2-73 freebase Form I, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, A2-73 Freebase Fumarate Salt Form I, A2-73 Freebase Fumarate Salt Form II, A2-73 Freebase Fumarate Salt Form III, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Dihydrogen Phosphate Form I, A2-73 Freebase Dihydrogen Phosphate Form II, A2- 73 Freebase Mesylate Form I, A2-73 Freebase Mesylate Form II, A2-73 Freebase Oxalate Form I, A2-73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Benzoate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase HBr Salt Form A and A2-73 Freebase HBr Salt Form B, A2-73 Freebase Maleate Salt Form S5, and A2-73 Freebase Maleate Salt Form S6. Details on the 49 103396107.1Docket No: 085102-844842 PCT A2-73 freebase salts may be found in WO 2019 / 200345. In another aspect, the Sigma-1 agonist is a co-crystal form comprising an A2-73 co-crystal with a tartaric acid, with a citric acid, and / or with a malic acid. In another aspect, the co-crystal is Crystal Form CSII of A2-73 and tartaric acid, Crystal Form CSIII of co-crystal of A2- 73 and citric acid, Crystal Form CSIV of co-crystal of A2-73 with malic acid and the co-crystals may be prepared by methods as detailed in WO 2023 / 208133. In another aspect, the Sigma-1 agonist is a racemic co-crystal disclosed and prepared in WO 2025 / 022317. The present disclosure encompasses various polymorphic forms and co-crystal forms of A2-73, A2-73 freebase, A2-73 freebase salts. The polymorphic forms may be prepared by solvent extraction or by supercritical fluid extraction (SCE). The crystal forms prepared from solvent extraction can be found in WO 2019 / 200345. The crystal forms prepared by SCE extraction can be found in WO 2017 / 013498. The present disclosure expressly encompasses the A2-73 Crystal Form I, A2-73 Crystal Form II and A2-73 Crystal Form III as prepared and characterized in WO 2017 / 013498. A2-73 Crystal Form I is a crystal with XRPD peaks as shown in FIG.1 of WO 2017 / 013498. A2-73 Crystal Form I is further characterized by scanning electron microscope (SEM) micrographs as shown in FIGs.2-3 of WO 2017 / 013498. A2-73 Crystal Form II is a crystal with XRPD peaks as shown in FIG.4 of WO 2017 / 013498. A2-73 Crystal Form II is also characterized by FTIR as shown in FIG.5 of WO 2017 / 013498. The SEM micrographs of A2-73 Crystal Form II is shown in FIG.7 of WO 2017 / 013498. A2-73 Crystal Form III is a crystal with XRPD peaks as shown in FIG.8 of WO 2017 / 013498. A2-73 Crystal Form III is characterized by FTIR as shown in FIG.9 of WO 2017 / 013498. A2-73 Crystal Form III is characterized by scanning electron microscope (SEM) micrograph as shown in FIG.11 of WO 2017 / 013498. The present disclosure also encompasses the polymorphic forms of A2-73 free base. The polymorphic form I of A2-73 freebase and its preparation can be found in WO 2019 / 200345. As an example, a crystal form of A2-73 freebase is the crystalline form characterized by XRPD pattern shown in FIG.16 of WO 2019 / 200345. And such crystalline form possesses particle shapes depicted in FIG.15 of WO 2019 / 200345. The present disclosure encompasses an enantiomer of A2-73 or a mixture of such enantiomer. The enantiomer may be an (+) or (-) enantiomer. The enantiomer refers to an optical pure or a substantial optical pure entity. The substantial optical pure entity refers to the opposite rotation entity may be presented in an amount of no more than 20%, such as at or about 0.1%, at 50 103396107.1Docket No: 085102-844842 PCT or about 0.5%, at or about 1%, at or about 2%, at or about 5%, at or about 8%, at or about 10%, at or about 12%, at or about 15%, at or about 18%, or at or about 20%. The present disclosure also expressly encompasses the (+) and (-) enantiomer disclosed and characterized in WO 2017 / 013496. The full disclosures of each of WO 2017 / 013496; WO 2017 / 013498; WO 2019 / 200345; WO 2023 / 208133; and WO 2025 / 022317 are hereby incorporated by reference herein in their entirety.

[0065] In yet another aspect of the present disclosure, a Sigma-1 receptor agonist is administered to the subject for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks. In another aspect, a Sigma-1 receptor agonist is administered to the subject daily, such as once daily, twice daily, and / or 3 times daily. In another aspect, a Sigma-1 receptor agonist is administered to the subject according to an intermittent regimen. In one aspect, the intermittent dosing regimen comprises at least two cycles, each cycle comprising (a) a dosing period during which the Sigma-1 receptor agonist and / or its composition is administered to said patient; and thereafter (b) a resting period. In one aspect, the dosing period and the resting period are of the same duration. In another aspect, the dosing period and the resting period are of different durations. In one aspect, the dosing period and the resting period is in the range of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days.

[0066] In yet another aspect of the present disclosure, a Sigma-1 receptor agonist therapy comprises A2-73 and its pharmaceutical composition thereof. In one aspect, a composition comprising A2-73 in a crystal form and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks. In another aspect, A2-73 is administered in about 50 mg daily for up to 11 weeks. Alternatively, A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.

[0067] In another aspect, the Sigma-1 receptor agonist may comprise ANAVEX® 19-144 (A19-144), having the chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)- 51 103396107.1Docket No: 085102-844842 PCT N-methylmethanamine hydrochloride. Without being bound by any theory, A19-144 is reported as a metabolite of A2-73. In the present disclosure A2-73 is a compound, which is subjected to enzymatic oxidation, reduction or hydrolysis under physiological conditions in the living body and is converted to A19-144 of the present disclosure. A19-144 may be in the forms of A19-144 freebase, A19-144 amorphous form, a A19-144 crystal. Such crystal may be prepared by methods and procedures disclosed in WO 2017 / 013498. Without being bound by theory, A19-144 is reported as a metabolite of A2-73. In the present disclosure A2-73 is a compound, which is subjected to enzymatic oxidation, reduction or hydrolysis under physiological conditions in the living body and is converted to A19-144 of the present disclosure. A19-144 may be in the forms of A19-144 freebase, A19-144 amorphous form, a A19- 144 crystal. Such crystal may be prepared by methods and procedures disclosed in WO 2017 / 013498. When the active pharmaceutical ingredient is A3-71 , a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 5 mg to about 30 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A3-71. The active pharmaceutical ingredient may be administered daily, twice daily, or three times daily. The duration of administration may be about 3-6 weeks, 6-11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or chronically. For example, A2-73 or A3-71 may be administered in an amount of about 40 mg to about 60 mg once daily for about 6-11 weeks or is administered in about 50 mg daily for up to 11 weeks. A3-71 or A2-73 may also be administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily. A3-71 or A2-73 may also be administered daily in an escalating dose starting from about 5 mg to about 10 mg to ending at about 20 mg to about 30 mg once daily.

[0068] Yet in another aspect, the Sigma-1 receptor agonist may comprise ANAVEX®1-41 (A1-41), having the chemical name of tetrahydro-N, N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride. Yet in another aspect, the Sigma-1 receptor agonist may comprise AV1066, having the chemical name of 1-(3- 4(((1R,3S,5S)-adamantan-1-yl) (pheny)methyl) propyl)-4-methylpiperazine. 52 103396107.1Docket No: 085102-844842 PCT ANAVEX®3-71 (A3-71, AF-710B) has a chemical name of 1-(2,8-dimethyl-1-thia-3,8- diazaspiro 4.5 decan-3-yl)-3-(1H-indol-3-yl) propan-1-one.

[0069] As in all the methods disclosed herein, the Sigma-1 receptor agonist may comprise one or more of ANAVEX®2-73 (A2-73), ANAVEX®19-144, ANAVEX®1-41, AV1066, ANAVEX®3-71, PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L- 687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.

[0070] There are two main challenges in the design of clinical trials for neurological diseases: their length and cost, and their use of physiological endpoints for which cognitive and other testing are difficult to reproduce. a A2-73 drug therapy by administering A2-73 freebase, a crystal form of A2-73 freebase, a salt of A2-73 freebase, a crystal form of A2-73 freebase salt, A2-73 amorphous form, a crystal form of A2-73, an enantiomer or stereoisomer of A2-73, a co-crystal of A2-73, an enantiomer or stereoisomer of A2-73 freebase, an enantiomer or stereoisomer of A2- 73 freebase salt.

[0071] In one aspect, the crystal form is selected from A2-73 freebase Form I, A2- 73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, A2-73 Freebase Fumarate Salt Form I, A2-73 Freebase Fumarate Salt Form II, A2-73 Freebase Fumarate Salt Form III, A2-73 Freebase Sulfate Form I, A2-73 Freebase Sulfate Form II, A2-73 Freebase Dihydrogen Phosphate Form I, A2-73 Freebase Dihydrogen Phosphate Form II, A2- 73 Freebase Mesylate Form I, A2-73 Freebase Mesylate Form II, A2-73 Freebase Oxalate Form I, A2-73 Freebase Oxalate Form II, A2-73 Freebase Oxalate Form III, A2-73 Freebase Benzoate Form I, A2-73 Freebase Edisylate Form I, A2-73 Freebase HBr Salt Form A and A2-73 Freebase HBr Salt Form B, A2-73 Freebase Maleate Salt Form S5, and A2-73 Freebase Maleate Salt Form S6. Details on the A2-73 freebase salts may be found in WO 2019 / 200345. In another aspect, the Sigma-1 agonist is a co-crystal form comprising an A2-73 co-crystal with a tartaric acid, with a citric acid, and / or with a malic acid. In another aspect, the co-crystal is Crystal Form CSII of A2-73 and tartaric acid, Crystal Form CSIII of co-crystal of A2- 73 and citric acid, Crystal Form CSIV of co-crystal of A2-73 with malic acid and the co-crystals may be prepared by methods as detailed in WO 2023 / 208133. In another 53 103396107.1Docket No: 085102-844842 PCT aspect, the Sigma-1 agonist is a racemic co-crystal disclosed and prepared in WO 2025 / 022317. The present disclosure encompasses various polymorphic forms and co-crystal forms of A2-73, A2-73 freebase, A2-73 freebase salts. The polymorphic forms may be prepared by solvent extraction or by supercritical fluid extraction (SCE). The crystal forms prepared from solvent extraction can be found in WO 2019 / 200345. The crystal forms prepared by SCE extraction can be found in WO 2017 / 013498. The present disclosure expressly encompasses the A2-73 Crystal Form I, A2-73 Crystal Form II and A2-73 Crystal Form III as prepared and characterized in WO 2017 / 013498. A2-73 Crystal Form I is a crystal with XRPD peaks as shown in FIG.1 of WO 2017 / 013498. A2-73 Crystal Form I is further characterized by scanning electron microscope (SEM) micrographs as shown in FIGs.2-3 of WO 2017 / 013498. A2-73 Crystal Form II is a crystal with XRPD peaks as shown in FIG.4 of WO 2017 / 013498. A2-73 Crystal Form II is also characterized by FTIR as shown in FIG.5 of WO 2017 / 013498. The SEM micrographs of A2-73 Crystal Form II is shown in FIG.7 of WO 2017 / 013498. A2-73 Crystal Form III is a crystal with XRPD peaks as shown in FIG.8 of WO 2017 / 013498. A2-73 Crystal Form III is characterized by FTIR as shown in FIG.9 of WO 2017 / 013498. A2-73 Crystal Form III is characterized by scanning electron microscope (SEM) micrograph as shown in FIG.11 of WO 2017 / 013498. The present disclosure also encompasses the polymorphic forms of A2-73 free base. The polymorphic form I of A2-73 freebase and its preparation can be found in WO 2019 / 200345. As an example, a crystal form of A2-73 freebase is the crystalline form characterized by XRPD pattern shown in FIG.16 of WO 2019 / 200345. And such crystalline form possesses particle shapes depicted in FIG.15 of WO 2019 / 200345. The present disclosure encompasses an enantiomer of A2-73 or a mixture of such enantiomer. The enantiomer may be an (+) or (-) enantiomer. The enantiomer refers to an optical pure or a substantial optical pure entity. The substantial optical pure entity refers to the opposite rotation entity may be presented in an amount of no more than 20%, such as at or about 0.1%, at or about 0.5%, at or about 1%, at or about 2%, at or about 5%, at or about 8%, at or about 10%, at or about 12%, at or about 15%, at or about 18%, or at or about 20%. The present disclosure also expressly encompasses the (+) and (-) enantiomer disclosed and characterized in WO 2017 / 013496. The full disclosures of each of WO 2017 / 013496; WO 2017 / 013498; WO 2019 / 200345; WO 2023 / 208133; and WO 2025 / 022317 are hereby incorporated by reference herein in their entirety.. 54 103396107.1Docket No: 085102-844842 PCT

[0072] In another aspect, the Sigma-1 receptor agonist may comprise ANAVEX 19-144 (A19-144), having the chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)- N-methylmethanamine hydrochloride. Without being bound by any particular theory, A19-144 is reported as a metabolite of A2-73. In the present disclosure A2-73 is a compound, which is subjected to enzymatic oxidation, reduction or hydrolysis under physiological conditions in the living body and is converted to A19-144 of the present disclosure. A19-144 may be in the forms of A19-144 free base, A19-144 amorphous form, a A19-144 crystal. Such crystals may be prepared by methods and procedures disclosed in WO 2017 / 013498.

[0073] In another aspect, the Sigma-1 receptor agonist comprises AV1066, having a chemical name of 1-(3- 4(((1 R,3S,5S)-adamantan-1- yl)(pheny)methyl)propyl)-4-methylpiperazine. In yet another aspect, the Sigma-1 receptor agonist comprises ANAVEX®3-71 (A3-71, AF-710B), having chemical name of 1-(2,8-dimethyl-1-thia-3,8- diazaspiro4.5decan-3-yl)-3-(1 H-indol-3-yl) propan-1 - one. In another aspect, the Sigma-1 receptor agonist comprises their amorphous form, a crystal form therefore, an enantiomer thereof, or a prodrug thereof, or a combination thereof.

[0074] In any of the methods, the Sigma-1 receptor agonist therapy comprises a crystal of A2-73 or A2-73 free base and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks. For example, the crystal of A2- 73 or A2-73 free base is administered in about 50 mg daily for up to 11 weeks. Or A2-73 or A2-73 free base is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks. In one aspect, A2- 73 is administered to the subject for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks. In another aspect, a Sigma-1 receptor agonist is administered to the subject daily, such as once daily, twice daily, and / or 3 times daily. In another aspect, a Sigma-1 receptor agonist is administered to the subject according to an intermittent regimen. In one aspect, the intermittent dosing regimen comprises at least two cycles, each cycle comprising (a) a dosing period during which the Sigma-1 receptor agonist and / or its composition is administered to said patient; and thereafter (b) a 55 103396107.1Docket No: 085102-844842 PCT resting period. In one aspect, the dosing period and the resting period are of the same duration. In another aspect, the dosing period and the resting period are of different durations. In one aspect, the dosing period and the resting period is in the range of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15 days, and 14 days.

[0075] In yet another aspect of the present disclosure, a Sigma-1 receptor agonist therapy comprises A2-73 and its pharmaceutical composition thereof. In one aspect, a composition comprising A2-73 in a crystal form and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks. In another aspect, A2-73 is administered in about 50 mg daily for up to 11 weeks. Alternatively, A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.

[0076] In another aspect, the Sigma-1 receptor agonist may comprise ANAVEX 19-144 (A19-144), having the chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)- N-methylmethanamine hydrochloride. Without being bound by any particular theory, A19-144 is reported as a metabolite of A2-73. In the present disclosure A2-73 is a compound, which is subjected to enzymatic oxidation, reduction or hydrolysis under physiological conditions in the living body and is converted to A19-144 of the present disclosure. A19-144 may be in the forms of A19-144 free base, A19-144 amorphous form, and A19-144 crystal. Such crystal may be prepared by methods and procedures disclosed in WO 2017 / 013498. When the active pharmaceutical ingredient is A3-71, a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 5 mg to about 30 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A3-71. The active pharmaceutical ingredient may be administered daily, twice daily, or three times daily. The duration of administration may be about 3-6 weeks, 6-11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or chronically. For example, A2-73 or A3-71 may be administered in an amount of about 40 mg to about 60 mg once daily for about 6-11 56 103396107.1Docket No: 085102-844842 PCT weeks or is administered in about 50 mg daily for up to 11 weeks. A3-71 or A2-73 may also be administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily.

[0077] Other methods of administering the Sigma-1 receptor agonists including, for example A2-73 and its various forms, can be found in, e.g., WO 2014 / 155138; WO 2016 / 064711; WO 2017 / 013496; WO 2017 / 013498; WO 2017 / 132127; WO 2018 / 231216; WO 2019 / 079794; U.S. Patent No.9,750,746; U.S. Patent No. 10,413,519; U.S. Patent No.10,426,754; U.S. Patent No.10,441,563; U.S. Patent No.10,507,196; U.S. Patent No.11,071,723; and U.S. Patent No.11,617,734; the disclosures of each of which are hereby incorporated by reference herein in their entirety. IV. Methods of Treatment

[0078] One aspect of the present disclosure encompasses methods of personalized therapy or Precision Medicine by monitoring the treatment effectiveness in a subject by administering a therapeutically effective amount of a Sigma-1 receptor agonist, then analyzing the changes in the subject’s EEG profiles. EEG profiles include multiple parameters, such as waves of alpha, beta, delta, and theta, their relative strength, shape, ratio, and / or spike-and-wave complexes. The therapy delivered by the Sigma-1 receptor agonist would be deemed effective and should continue if EEG abnormalities are corrected or changed. If on the other hand, there is no effective correction or normalization of EEG, the therapy is deemed NOT effective, and a change of therapy or supplementation with another therapy would be recommended. The disorder or disease treated by a Sigma-1 receptor agonist including, but not limited to, Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X- syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli-Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, 57 103396107.1Docket No: 085102-844842 PCT schizophrenia, spina bifida, Tourette's syndrome, , Attention-deficit Disorder (ADD), Attention-deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof.

[0079] The Sigma-1 receptor agonist may comprise ANAVEX 2-73 (A2-73), ANAVEX 19-144 (A19-144), ANAVEX1-41 (A1-41), AV1066, ANAVEX3-71 (A3-71), PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof. In one aspect, the treatment is for Parkinson’s Disease, Parkinson’s disease with dementia, or for treating Rett Syndrome.

[0080] Another aspect of the present disclosure encompasses a method of determining if a subject is having or is suspected of having a neurodegenerative or neurodevelopmental disorder. The said disease or disorder is for example selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio- facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X- syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli-Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, Attention-deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof. In one aspect, the method comprises (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a period of administering with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the period of administering; and (c) concluding the subject having or is suspect of having the neurodegenerative or neurodevelopmental disorder when (b) demonstrates any one 58 103396107.1Docket No: 085102-844842 PCT of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady- State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region. The method further comprises continued the subject with the Sigma-1 receptor agonist therapy.

[0081] Yet another aspect of the present disclosure relates to use the gene profile as a surrogate clinical trial end-point. The clinical trial wherein the present disclosure may find utility is any interventional trials for disease treatment, and such trial may be in any phase, such as Phase 1, Phase 2 and Phase 3 clinical trials, as long as a clinical endpoint is required. Clinical endpoints are measurable events, outcomes, or change in pathological biomarkers that can help determine whether a medical intervention, such as a drug therapy, is benefiting patients or bringing desirable outcomes. Clinical endpoints can be primary or secondary. A clinical trial may have multiple primary endpoints, and / or multiple secondary endpoints. Phase 1 studies are performed to find the highest dose of the new treatment that can be given safely to human being without causing severe side effects. These studies also help to decide on the best way to give the new treatment. Phase 1 trials may only open to healthy human subjects but may have endpoint measurements.

[0082] In one aspect, the Sigma-1 receptor agonist comprises A2-73 in the forms of A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof. And the therapeutically effective amount of A2-73 comprises A2-73 in an amount of 0.5-100 mg per day, such 10-50 mg per day. A2-73 (blarcamesine), the therapeutically effective amount of A2-73 can range from about 0.5 mg to about 20 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. The therapeutically effective amount of A2-73 can range from about 0.5 mg / day to about 100 mg / day, from about 1 to about 60 mg / day, from about 20 to about 50 mg / day, from about 20 to about 30 mg / day, or from about 15 to about 25 mg / day. Administering the anti-neurodegenerative effective amount of A2- 73 can provide blood levels of about 10 ng / ml, about 12 ng / ml of A2-73. 59 103396107.1Docket No: 085102-844842 PCT

[0083] A2-73 can be administered to the subject daily or more than once daily. Further, A2-73 can be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. A2- 73 can be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months. A2-73 can also be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspects, A2-73 is administered over a period of about 6 weeks, 8 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 57 weeks, about 148 weeks, about 208 weeks, indefinitely, or until resolution of the condition being treated. In one aspect, A2-73 is administering through an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, or a topical administration. In yet another aspect, the A2-73 treatment period is about 12 weeks or less. In yet another aspect, the treatment period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0084] Other methods of administering the Sigma-1 receptor agonists including, for example A2-73 and its various forms, can be found in, e.g., WO 2014 / 155138; 60 103396107.1Docket No: 085102-844842 PCT WO 2016 / 064711; WO 2017 / 013496; WO 2017 / 013498; WO 2017 / 132127; WO 2018 / 231216; WO 2019 / 079794; U.S. Patent No.9,750,746; U.S. Patent No. 10,413,519; U.S. Patent No.10,426,754; U.S. Patent No.10,441,563; U.S. Patent No.10,507,196; U.S. Patent No.11,071,723; and U.S. Patent No.11,617,734; the disclosures of each of which are hereby incorporated by reference herein in their entirety.

[0085] In another aspect, the Sigma-1 receptor agonist may comprise ANAVEX 19-144 (A19-144), having the chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)- N-methylmethanamine hydrochloride. Without being bound by any particular theory, A19-144 is reported as a metabolite of A2-73. In the present disclosure A2-73 is a compound, which is subjected to enzymatic oxidation, reduction or hydrolysis under physiological conditions in the living body and is converted to A19-144 of the present disclosure. A19-144 may be in the forms of A19-144 free base, A19-144 amorphous form, a A19-144 crystal. Such crystal may be prepared by methods and procedures disclosed in PCT / IB2016 / 001181. The effective amount of 19-144 may comprise an amount of 0.5-100 mg per day, such as 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg per day. In one aspect, the therapeutically effective amount of A19-144 may range from about 0.5 mg to about 20 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg. The therapeutically effective amount of A2-73 can range from about 0.5 mg / day to about 100 mg / day, from about 1 to about 60 mg / day, from about 20 to about 50 mg / day, from about 20 to about 30 mg / day, or from about 15 to about 25 mg / day. Administering the anti-neurodegenerative effective amount of A19-144 can provide blood levels of about 10 ng / ml, about 12 ng / ml of A2-73.

[0086] Yet in another aspect, the Sigma-1 receptor agonist may comprise A1-41, AV1066, ANAVEX3-71 (A3-71, AF-710B, having a chemical name of 1-(2,8-dimethyl- 1-thia-3,8-diazaspiro 4.5 decan-3-yl)-3-(1H-indol-3-yl) propan-1-one), or an amorphous form thereof, a crystal form thereof, a salt thereof. In one aspect, the Sigma-1 receptor agonist comprises A3-71, and it is administered in a composition comprising from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 5 mg to about 30 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to 61 103396107.1Docket No: 085102-844842 PCT about 3 g of A3-71. The composition may be administered daily, twice daily, or three times daily. The duration of administration may be about 3-6 weeks, 6-11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or chronically. For example, A2-73, A19-144, A1-14, AV1006 or A3-71 may be administered in an amount of about 40 mg to about 60 mg once daily for about 6-11 weeks, or is administered in about 50 mg daily for up to 11 weeks. A3-71 or A2-73 may also be administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily. V. Pharmaceutical Compositions and Formulations

[0087] One aspect of the disclosure encompasses a pharmaceutical composition and formulations comprising a neurodegenerative agent and / or a Sigma-1 receptor agonist. A pharmaceutical formulation comprises a therapeutically effective amount of Sigma-1 receptor agonists and any pharmaceutically acceptable salt(s) thereof. The active pharmaceutical ingredient can be an organic molecule, an inorganic molecule, a protein, a polypeptide, an antibody, an antibody fragment, an RNA or a DNA. When the active pharmaceutical ingredient is an organic molecule, it can exist as a crystal form, or an amorphous form. When the active pharmaceutical ingredient is an organic molecule and has at least one chiral center, the active can be either a racemic form, or a crystal or polymorphic form.

[0088] Pharmaceutically acceptable salts of the Sigma-1 receptor agonists disclosed herein include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.

[0089] In one aspect, the Sigma-1 receptor agonist is administered through an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a 62 103396107.1Docket No: 085102-844842 PCT buccal administration, a rectal administration, a vaginal administration, or a topical administration. In yet another aspect, the treatment period is about 12 weeks or less. In yet another aspect, the treatment period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks. In yet another aspect, the Sigma-1 receptor agonist therapy is administered daily. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer. In yet another aspect, the Sigma-1 receptor agonist therapy is selected from A2-73 Crystal Form I, (-) A2-73 enantiomer, and any combination thereof. In one aspect, the Sigma-1 receptor agonist therapy is administered daily in an amount of about 1 mg to about 100 mg. In another aspect, the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg. In yet another aspect, the Sigma-1 receptor agonist therapy is A2-73 in an oral solution, and the A2-73 is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 30 mg and ending at about 50 mg.

[0090] When the active pharmaceutical ingredient is ANAVEX 2-73 (A2-73), a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A2-73. Formulations comprising A2-73 can be found in, e.g., U.S. Patent No.9,750,746; U.S. Patent No.10,413,519; U.S. Patent No.10,426,754; U.S. Patent No. 10,441,563; U.S. Patent No.10,507,196; U.S. Patent No.11,071,723; and U.S. Patent No.11,617,734; the disclosures of each of which are hereby incorporated by reference herein in their entirety.

[0091] The active pharmaceutical ingredient, such as a Sigma-1 receptor agonist, can be formulated and administered to a subject by several different means. For instance, a composition can generally be administered parenterally, intraperitoneally, intravascularly, transdermal, subcutaneously, or intrapulmonary in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired. The term parenteral as used 63 103396107.1Docket No: 085102-844842 PCT herein includes subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection, or infusion techniques. Formulation of pharmaceutical compositions is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).

[0092] A pharmaceutical composition and / or formulation comprising a Sigma-1 receptor agonist can optionally comprise one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof. One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.

[0093] The active pharmaceutical ingredient can in general be formulated for improving patient compliance, preventing a subject from removing the drug-delivery device. For instance, Sigma-1 receptor agonists could be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery. Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and / or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months.

[0094] Extended-release formulations could be used for substantially continuous delivery of drug at a preselected rate. For example, for crystalline A2-73, the drug can be delivered at a rate of from about 1 mg to about 100 mg / day, from about 40 to about 60 mg / day, or from about 10 to about 30 mg / day. Appropriate amounts of crystalline A2-73 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended-release formulation, the delivery mechanism, the particular formulation, and the relative potency of the drug among other factors. 64 103396107.1Docket No: 085102-844842 PCT Binders

[0095] Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.

[0096] The binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art. Alternatively, the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation. Diluents

[0097] Non-limiting examples of diluents (also referred to as “fillers” or “thinners”) include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing. Disintegrants

[0098] Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid. 65 103396107.1Docket No: 085102-844842 PCT Preservatives

[0099] Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, o-aminobenzoic acid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-carotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p- coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, esculetin, esculin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate; morin, beta- naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phytic acid, phytylubichromel, pimento extract, propyl gallate, polyphosphates, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol), tocotrienols (i.e., alpha-, beta-, gamma- and delta-tocotrienols), tyrosol, vanilic acid, 2,6-di-tert- butyl-4-hydroxymethylphenol (i.e., Ionox 100), 2,4-(tris-3',5'-bi-tert-butyl-4'- hydroxybenzyl)-mesitylene (i.e., Ionox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof. 66 103396107.1Docket No: 085102-844842 PCT Flavor-Modifying Agents

[0100] Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like. Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0101] Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials. In other aspects, additional taste-masking agents contemplated are those described in U.S. Pat. Nos.4,851,226; 5,075,114; and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0102] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic 67 103396107.1Docket No: 085102-844842 PCT sweetener 3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof. Lubricants and Glidants

[0103] The lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition. As a glidant, the lubricant facilitates removal of solid dosage forms during the manufacturing process. Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The pharmaceutical composition will generally comprise from about 0.01% to about 10% by weight of a lubricant. In some aspects, the pharmaceutical composition will comprise from about 0.1% to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant. Dispersants

[0104] Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants. Colorants

[0105] Depending upon the aspect of the disclosure, it may be desirable to include a coloring agent. Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. pH Modifiers

[0106] Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate. 68 103396107.1Docket No: 085102-844842 PCT Chelating Agents

[0107] A chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, in order to inhibit the oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA). Antimicrobial Agents

[0108] An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite. Release-Controlling polymers

[0109] Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure. In one aspect, the release-controlling polymers may be used as a tablet coating. In other aspects, including but not limited to bilayer tablets, a release- controlling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold. Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.

[0110] Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl 69 103396107.1Docket No: 085102-844842 PCT polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2- pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof. Coatings

[0111] A solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, act as a moisture barrier, or buffer or modify pH. A “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof. The coating, when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form. For example, the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “controlled-release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged-release,” or combinations thereof. The “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.

[0112] The term “moisture barrier” as used herein is one which impedes or retards the absorption of moisture. Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition over time under highly humid conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall 70 103396107.1Docket No: 085102-844842 PCT within the USP definition and requirement for an enteric coat. Suitably, the moisture barrier may comprise an enteric and / or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.

[0113] Coating and matrix materials which may be used in accordance with the present disclosure are those known in the art for use in controlled-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i.e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12-hydroxystearl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di- or tristearate; myristyl alcohol, stearic acid, stearyl alcohol, and polyethyleneglycols; waxes; sugars and sugar alcohols.

[0114] The pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum / magnesium compounds, for example Al2O3·6MgO·CO2·12H2O, (Mg6Al2(OH)16CO3·4H2O), MgO·Al2O3·2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0115] A pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (GI) tract, e.g., the stomach or small intestine. When a pH- independent coating is desired, the coating is designed to achieve optimal release 71 103396107.1Docket No: 085102-844842 PCT regardless of pH-changes in the environmental fluid, e.g., the GI tract. When the coating is formulated to release a compound according to this disclosure in the intestines (especially the upper small intestines), the coating is often called an “enteric coating”. A pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate (e.g., Eudragit™); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein; and salts and combinations thereof. Oral tablets and capsules typically have coatings. VI. Dosage Forms

[0116] One aspect of the disclosure encompasses dosage forms of Sigma-1 receptor agonists. When the agonist is A2-73, for example, the dosage form can comprise from about 1 mg to about 50 g, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to about 500 mg, from about 50 to about 400 mg, from about 75 to about 150 mg, from about 150 to about 200 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73. For instance, the dosage form can comprise 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 or more mg of A2-73. In some aspects, dosage forms can comprise from about 1 mg to about 500 mg, or about 1 mg to about 100 mg of A2-73.

[0117] Dosage forms include those formulated for extended or slow release, and those formulated for immediate release. For example, an immediate release dosage form may include a crystalline form of A2-73 as the free base or as a A2-73 salt as disclosed herein. For example, a fast-dissolve oral dosage form may include for example an A2-73 salt, such as the HCl salt. Alternatively, a dosage form may 72 103396107.1Docket No: 085102-844842 PCT include a crystalline form of A2-73 as the free base or as a A2-73 salt formulated for inhalation drug delivery, either as a dry powder or aerosol spray.

[0118] Dosage forms also include those formulated for topical administration. For instance, a dosage form can be formulated as one or more of a gel, ointment, emulsion, microemulsion, solution, suspension, paste, gel, foam, spray, lotion, or cream. In one aspect, a topical administration dosage form is a transdermal patch. When the dosage form is formulated as a transdermal patch, the transdermal patch can contain from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, or from about 180 mg to about 220 mg of A2-73 freebase in crystalline form.

[0119] Dosage forms can alternatively be formulated for oral administration. Dosage forms formulated for oral administration can be tablets to swallow, chew, or dissolve in water or under the tongue, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications or syrups. In some aspects, the dosage form is an enteric coated oral formulation.

[0120] When the dosage form is an enteric coated oral formulation, the formulation can comprise from about 0.1 mg to about 60 mg A2-73 freebase, preferably from about 1 mg to about 50 mg A2-73 freebase.

[0121] An enteric coated oral formulation can also contain A2-73 salt in crystalline form. The A2-73 salt can be a fumarate salt, a sulfate salt, a mesylate salt, a dihydrogen phosphate salt, an edisylate salt, a benzoate salt, a hydrochloride salt, and an oxalate salt. In one aspect, the A2-73 salt is a fumarate salt. When the A2- 73 salt is a fumarate salt, the enteric coated oral formulation can comprise from about 0.1 to about 100 mg of A2-73 fumarate salt, preferably from about 1 mg to about 55 mg of A2-73 fumarate salt.

[0122] Dosage forms also encompass those formulated for subcutaneous and / or intramuscular injection. For example, an intramuscular dosage form may comprise A2-73 in the free base form, dissolved in an oil matrix for intramuscular injection, or alternatively prepared as a suspension of the free base for intramuscular injection. A dosage form formulated for subcutaneous or intramuscular injection may comprise A2-73 in a salt or free base form as disclosed herein, prepared as microspheres using methods known in the art. Alternatively, A2-73 in free base or salt form may be 73 103396107.1Docket No: 085102-844842 PCT coated, for example using Atomic Layer Deposition (ALD) techniques, with a thin layer coating such as a coating of zinc oxide, and used in a formulation for subcutaneous or intramuscular injection. Alternatively, A2-73 free base may be dissolved in a biodegradable polymer matrix, and then implanted subcutaneously (or used in a transdermal patch as detailed further below). VII. Kits for Medical Uses

[0123] One aspect of the present disclosure encompasses a kit for a medical use according to any of the monitoring, evaluating, or therapy selection methods disclosed herein. A kit for such uses includes one container for receiving and holding a Sigma-1 receptor agonist or a pharmaceutical composition thereof, and another containing for storing the accessory for EEG measurement. The kit ensures the storage of the Sigma-1 receptor agonist or the pharmaceutical composition in a safe, stable and durable way. The pharmaceutical composition comprises an effective amount of the Sigma-1 receptor agonist, such as A2-73, A2-73 crystals or A2-73 freebase. The kits provided herein generally include instructions for carrying out the methods disclosed herein or explaining the use of the kit components to perform any of the methods disclosed herein. Instructions included in the kits may be affixed to packaging material or may be included as a package insert. While the instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” may include the address of an internet site that provides the instructions.The instruction may be written with the medical practitioner and / or the patient as the intended reader.

[0124] In one aspect of the present disclosure, the kit may be used for various purposes, such as selection of a therapeutic agent for a subject, monitoring effectiveness of a Sigma-1 receptor agonist therapy, identification of a subject responsive to a Sigma-1 receptor agonist therapy, or determining if a subject is having, is suspected of having, or having an increased risk for developing a disorder or a disease. Such disorder or disease may include Alzheimer’s disease, Parkinson’s 74 103396107.1Docket No: 085102-844842 PCT disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, Rett syndrome, cerebral palsy, Angelman syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X- syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli-Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, Attention Deficiency Disorder (ADD), Attention-deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, and any combination thereof. DEFINITIONS

[0125] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which present disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in the present disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0126] When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0127] As various changes could be made in the above-described cells and methods without departing from the scope of the present disclosure, it is intended that all matter contained in the above description and in the examples given below, shall be interpreted as illustrative and not in a limiting sense. 75 103396107.1Docket No: 085102-844842 PCT

[0128] The term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like. The terms “comprising” and “including” as used herein are inclusive and / or open-ended and do not exclude additional, unrecited elements or method processes. The term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or items and those that do not materially affect the essential characteristics of the present disclosure.

[0129] As used herein, the terms “disease”, “disorder” or “dysfunction” are used interchangeably in the present disclosure. They refer to any condition, disorder or disease manifested as one or more physiological, physical and / or psychological symptoms or dysfunctions for which treatment is desirable, and includes previously and newly identified diseases, disorders or dysfunctions on any organs, tissues or biological activities. As used herein, the term “medical use” is any use or means related to restore, remedy, or preserve health or wellbeing of a subject.

[0130] As used herein, the term “subject” means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like).

[0131] As used herein, the administration of an agent or drug to a subject or patient includes self-administration and the administration by another. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

[0132] The publications discussed above are provided solely for their disclosure before the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such disclosure by virtue of prior disclosure. 76 103396107.1Docket No: 085102-844842 PCT EXAMPLES

[0133] The following examples are included to demonstrate the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the disclosure. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes could be made in the disclosure and still obtain a like or similar result without departing from the spirit and scope of the disclosure, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense. Example 1. Study Design

[0134] Fragile X syndrome (FXS) is characterized by cognitive impairment, behavioral abnormalities, and aberrant cortical processing including imbalanced excitation-inhibition. Translational electroencephalographic (EEG) biomarkers assessed in human and animal models of FXS were used to investigate the neural underpinnings of FXS and evaluating the efficacy of novel therapeutics. Sensory- evoked paradigms, such as the auditory steady-state response (ASSR), were used to evaluate neural processes (e.g., auditory processing) that have implications for higher-level cortical functions.

[0135] Notably, auditory processing deficits were observed in both individuals with FXS and the Fmr1 KO mouse model. Individuals with FXS were found to have enhanced gamma power and reduced inter-trial phase coherence, particularly at gamma frequencies, compared to healthy controls. In individuals with FXS intensified background gamma oscillations ("gamma noise“) may contribute to hypersensitivities and interfere with stimulus-evoked synchronization. These EEG abnormalities correlated with FXS phenotypes of social communication deficits and hypersensitivities.

[0136] ANAVEX®2-73 (A2-73, blarcamesine), an agonist of Sigma-1 receptor (SIGMAR1), has shown therapeutic effects against neurodevelopmental and neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Rett Syndrome. Fragile X syndrome (FXS), the most common inherited form of neurodevelopmental disability, is characterized by cognitive impairment, behavioral abnormalities, and other dysfunctions linked to 77 103396107.1Docket No: 085102-844842 PCT aberrant cortical processing. Electroencephalographic (EEG) abnormalities constitute biomarkers of cortical dysfunction may implicated in FXS subjects.

[0137] The current study used FXS mouse model (Fmr1 KO) and subjected the Fmr1 KO mice to the treatments of A2-73 in the oral doses of about 1 mg, about 10 mg and about 30 mg respectively. Effects of A2-73 on FXS-relevant EEG biomarkers were measured utilizing a multielectrode array applied to different brain regions shown in FIG.1A. As shown in FIG.1B, there were five testing groups: three groups of Fmr1 KO mice received three different orally administered (PO) doses of A2-73 (1 mg / kg / day, n=10; 10 mg / kg / day, n=15; and 30 mg / kg / day, n=15); one group of Fmr1 KO (n=10) mice received vehicle; and one group of wild-type mice (n=10) also received vehicle. EEG effects were monitored on resting state power (from delta to gamma frequencies) and network synchronization (inter-trial phase coherence, ITPC) on three auditory stimulation paradigms (chirp, auditory steady-state response ASSR at 40 Hz and ASSR at 80 Hz, respectively). Example 2. Results

[0138] Fmr1 KO mice treated with A2-73 showed improvement in all study parameters in a dose-dependent manner as reflected in FIGS.2A-2C, 3A-3C, 4A-4C and 5A-5C. Specifically, effects were greatest at 30 mg / kg dose. Significant reductions in EEG resting state power observed in all cortical regions, Ratio of Fmr1 KO post-treatment (black bars) to Fmr1 KO pre-treatment (white bars) represented improved EEG resting state power across frequency bands for distinct brain regions with statistical significance, as shown in FIGS.2A-2C. Further, significant improvements in chirp synchronization (ITPC) were observed in all cortical regions, as shown in FIGS.3A-3C. Significant improvements in 40 Hz ASSR synchronization (ITPC) were observed in all regions except for the left and right medial regions, as shown in FIGS.4A-4C. Significant improvements in 80 Hz ASSR synchronization (ITPC) were observed in left and right medial regions, as shown in FIGS.5A-5C. In summary as shown in Table 1, the resting state reductions involved all frequencies, including suppression of the FXS-distinctive elevation in the gamma band. Significant improvements in synchronization (ITPC) were observed for chirp in all cortical regions; while for 40 Hz ASSR and for 80 Hz ASSR, improvements appeared in frontal and temporal regions and in medial regions, respectively. Further, dose- 78 103396107.1Docket No: 085102-844842 PCT dependent improvements were observed in all tests, with the greatest effects observed at 30 mg / kg / day PO. TABLE 1: Summary of Response Difference versus DosesExample 3: Discussion

[0139] These mice results were interpreted for human applicability. It was noted that both humans and Fmr1 KO mice exhibited enhanced resting gamma power in disease state, and A2-73 decreased (improved) FXS related-elevated resting gamma power in all cortical regions. Further, both human and Fmr1 KO mice exhibited reduced inter-trial phase coherence (ITPC) response to auditory chirp. It was observed that A2-73 increased (improved) ITPC in all cortical regions. It was also noted that increases in ITPC in medial regions in the ASSR 40 Hz disappeared when doses increased from 10 mg to 30 mg, while all other EEG parameters improved in a dose dependent manner. The improvement in 40 Hz ASSR ITPC by A2-73 was much stronger in the frontal and temporal lobes, while 80 Hz ASSR ITPC (high gamma 79 103396107.1Docket No: 085102-844842 PCT band) by A2-73 only showed improvement in medial regions. This regional difference indicated that A2-73 may have a signature effect in these regions, in addition to brain-wide effects.

[0140] In summary, significant improvements were observed in resting power and ITPC, a measure of cortical circuit synchronization, in a dose-dependent manner. These improvements demonstrate target engagement of A2-73 (blarcamesine) and its capacity to correct multiple EEG biomarkers of cortical dysfunction in the Fmr1 KO mouse model. Notably A2-73’s effect on 40 Hz ASSR ITPC, a paradigm reflecting parvalbumin GABAergic deficits, demonstrated a potentially translatable improvement in the well-established feature of GABAergic dysfunction in FXS. Given that these biomarkers represent fundamental mechanisms underlying cognitive and behavioral abnormalities in FXS and that they are shared by FXS mouse models and affected individuals, the present findings supported various clinical potentials of A2- 73 against FXS as well as other neurodevelopmental or neurodegenerative disorders. For example, in both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden. Altogether, the present disclosure established reliable relationships between quantitative EEG biomarkers and clinical phenotypes / outcomes in various neurodevelopmental or neurodegenerative disorders, such as when treated by a Sigma-1 receptor agonist. 80 103396107.1

Claims

Docket No: 085102-844842 PCT WHAT IS CLAIMED IS 1. A method of treating a neurodevelopmental disorder with a Sigma-1 receptor agonist therapy in a subject in need thereof, the method comprising: (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject at the end of a treatment period with a Sigma-1 Receptor agonist; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting the treatment period; (c) continuing the treatment with the Sigma-1 receptor agonist therapy in the subject when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region.

2. The method of claim 1 further comprising discontinuing the Sigma-1 receptor agonist therapy in the subject when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG.

3. The method of claim 2, wherein when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of: (i) switching the subject to a different Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist.

4. The method of any one of claims 1-3, wherein the Sigma-1 receptor agonist is selected from: 81 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l- one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, and any combination thereof.

5. The method of any one of claims 1-4, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; 82 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; 83 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and any combination thereof.

6. The method of any one of claims 1-5, wherein the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration.

7. The method of any one of claims 1-6, wherein the treatment period is about 12 weeks or less.

8. The method of any one of claims 1-7, wherein the treatment period is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks.

9. The method of any one of claims 1-8, wherein the Sigma-1 receptor agonist is administered daily. 84 103396107.1Docket No: 085102-844842 PCT 10. The method of any one of claims 1-9, wherein the Sigma-1 receptor agonist is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer.

11. The method of any one of claims 1-10, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in Crystal Form I.

12. The method of any one of claims 1-10, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in Crystal Form I.

13. The method of any one of claims 1-12, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 1 mg to about 100 mg.

14. The method of any one of claims 1-12, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 5 mg to about 60 mg.

15. The method of any one of claims 1-12, wherein the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg.

16. The method of any preceding claim, wherein the Sigma-1 receptor agonist comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in an oral solution, and wherein the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 5 mg to about 10 mg and ending at about 20 mg to about 30 mg.

17. The method of any preceding claim, wherein the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an 85 103396107.1Docket No: 085102-844842 PCT eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome.

18. The method of any preceding claim, wherein the neurodevelopmental disease is Fragile X Syndrome.

19. The method of any preceding claim, wherein the neurodevelopmental disease is Rett Syndrome.

20. The method of any preceding claim, wherein the subject is a pediatric, a teenager, or an adult human.

21. The method of any preceding claim, wherein the medial region comprises the left medial region or the right medial region.

22. The method of any preceding claim, wherein the non-medial region comprises a cortical region or a lobe region.

23. The method of any preceding claim, wherein the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof.

24. The method of any preceding claim, wherein the Test EEG or Control EEG comprises scalp EEG or intracranial EEG.

25. A method of selecting a Sigma-1 receptor agonist for treating a neurodevelopmental disorder in a subject in need thereof, the method comprising: (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the subject for a trial period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before starting of the trial period; 86 103396107.1Docket No: 085102-844842 PCT (c) selecting the Sigma-1 receptor agonist for the subject, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region.

26. The method of claim 25, further comprising discontinuing the Sigma-1 receptor agonist therapy for the subject when none of (i)–(iv) in (c) are observed on the Test EEG compared to the Control EEG.

27. The method of claim 25, wherein when none of (i)–(iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises one of: (i) switching the subject to another Sigma-1 receptor agonist; (ii) switching the subject to another neurodevelopmental drug therapy; and (iii) switching the subject to a combination therapy comprising the Sigma-1 receptor agonist.

28. The method of any one of claims 25-27, wherein the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (A19-144 freebase); 87 103396107.1Docket No: 085102-844842 PCT (1-(2,8-dimethyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l- one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, and any combination thereof.

29. The method of any one of claims 25-27, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; 88 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; 89 103396107.1Docket No: 085102-844842 PCT a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and any combination thereof.

29. The method of any one of claims 25-28, wherein the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration.

30. The method of any one of claims 25-29, wherein the trial period is about 12 weeks or less.

31. The method of any one of claims 25-29, wherein the trial period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.

32. The method of any one of claims 25-31, wherein the Sigma-1 receptor agonist is administered daily.

33. The method of any one of claims 22-30, wherein the Sigma-1 receptor agonist is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer.

34. The method of any one of claims 25-33, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in Crystal Form I. 90 103396107.1Docket No: 085102-844842 PCT 35. The method of any one of claims 25-33, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in Crystal Form I.

36. The method of any one of claims 25-35, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 1 mg to about 100 mg.

37. The method of any one of claims 25-35, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 5 mg to about 60 mg.

38. The method of any one of claims 25-35, wherein the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg.

39. The method of any one of claims 25-38, wherein the Sigma-1 receptor agonist comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in an oral solution, and wherein the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 5 mg to about 10 mg and ending at about 20 mg to about 30 mg.

40. The method of any one of claims 25-39, wherein the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome.

41. The method of any one of claims 25-40, wherein the neurodevelopmental disease is Fragile X Syndrome. 91 103396107.1Docket No: 085102-844842 PCT 42. The method of any one of claims 25-40, wherein the neurodevelopmental disease is Rett Syndrome.

43. The method of any one of claims 25-42, wherein the subject is a pediatric, a teenager or an adult human.

44. The method of any one of claims 25-43, wherein the medial region comprises the left medial region or the right medial region.

45. The method of any one of claims 25-43, wherein the non-medial region comprises a cortical region or a lobe region.

46. The method of any one of claims 25-44, wherein the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof.

47. The method of any one of claims 25-46, wherein the Test EEG or Control EEG comprises scalp EEG or intracranial EEG.

48. A method of using an encephalography (EEG) as an endpoint for a trial test of a Sigma-1 receptor agonist against a neurodevelopmental disorder in a trial subject, the method comprising: (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the trial subject for a trial period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the trial subject before starting of the trial period; (c) identifying the trial subject as meeting the trial endpoint, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; 92 103396107.1Docket No: 085102-844842 PCT (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region.

49. The method of claim 48, further comprising labeling the trial subject as failing to meet the surrogate endpoint when none of (i)–(iv) in (c) are observed on the Test EEG compared to the Control EEG.

50. The method of claim 44, wherein when none of (i) to (iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises: (i) switching the trial subject to another Sigma-1 receptor agonist; (ii) switching the trial subject to another neurodevelopmental drug therapy; or (iii) switching the trial subject to a combination therapy comprising the Sigma-1 receptor agonist.

51. The method of any one of claims 48-50, wherein the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l- one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, and any combination thereof. 93 103396107.1Docket No: 085102-844842 PCT 52. The method of any one of claims 48-51, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; 94 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and 95 103396107.1Docket No: 085102-844842 PCT any combination thereof.

53. The method of any one of claims 48-52, wherein the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration.

54. The method of any one of claims 48-53, wherein the trial period is about 12 weeks or less.

55. The method of any one of claims 48-54, wherein the trial period is selected from about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.

56. The method of any one of claims 48-55, wherein the Sigma-1 receptor agonist is administered daily.

57. The method of any one of claims 48-56, wherein the Sigma-1 receptor agonist is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer.

58. The method of any one of claims 48-57, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in Crystal Form I.

59. The method of any one of claims 48-57, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in Crystal Form I.

60. The method of any one of claims 48-58, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 1 mg to about 100 mg. 96 103396107.1Docket No: 085102-844842 PCT 61. The method of any one of claims 48-58, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 5 mg to about 60 mg.

62. The method of any one of claims 48-58, wherein the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg.

63. The method of any one of claims 48-62, wherein the Sigma-1 receptor agonist comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in an oral solution, and wherein the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 5 mg to about 10 mg and ending at about 20 mg to about 30 mg.

64. The method of any one of claims 48-63, wherein the neurodevelopmental disorder is selected from Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith-Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli-Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome.

65. The method of any one of claims 48-64, wherein the neurodevelopmental disease is Fragile X Syndrome.

66. The method of any one of claims 48-64, wherein the neurodevelopmental disease is Rett Syndrome.

67. The method of any one of claims 48-66, wherein the subject is a pediatric, a teenager or an adult human. 97 103396107.1Docket No: 085102-844842 PCT 68. The method of any one of claims 48-67, wherein the medial region comprises the left medial region or the right medial region.

69. The method of any one of claims 48-68, wherein the non-medial region comprises a cortical region or a lobe region.

70. The method of any one of claims 48-69, wherein the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof.

71. The method of any one of claims 48-70, wherein the EEG comprises scalp EEG or intracranial EEG.

72. A method of using a Sigma-1 receptor agonist in assessing a disease risk in a subject, the method comprising: (a) obtaining or having obtained a test electroencephalography (Test EEG) from the subject after administering the Sigma-1 receptor agonist to the subject for a test period; (b) comparing the Test EEG with a predetermined control electroencephalography (Control EEG), wherein the Control EEG was obtained for the subject before the start of the test period; (c) identifying the subject as at a risk for developing the disease, when the comparison in (b) demonstrates any one of the following in the Test EEG compared to the Control EEG: (i) reduction in EEG resting state power in a brain cortical region; (ii) improvement in chirp synchronization in a brain cortical region; (iii) improvement in 40 Hz Auditory Steady-State Response (ASSR) synchronization in a brain non-medial region; and (iv) improvement in 80 Hz ASSR synchronization in a brain medial region; wherein the disease is selected from the group consisting of Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, Angelman syndrome, Smith- Magenis syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, Fragile X Syndrome, ICF syndrome, Neurofibromatosis, Rett syndrome, Smith-Lemli- Opitz syndrome, an addictive disorder, ADHD, an anxiety disorder, Asperger's 98 103396107.1Docket No: 085102-844842 PCT syndrome, an autistic disorder, an eating disorder, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressive illness, mental retardation, schizophrenia, spina bifida, and Tourette's syndrome.

73. The method of claim 72, further comprising assessing the subject having no current risk for the disease when none of (i)–(iv) in (c) are observed on the Test EEG compared to the Control EEG.

74. The method of any one of claims 72-73, wherein when none of (i)–(iv) in (c) are observed on the Test EEG compared to the Control EEG, the method further comprises: (i) recommending another diagnostic method to the subject; or (ii) starting a preventive therapy for the subject comprising the Sigma-1 receptor agonist.

75. The method of claims 72-74, wherein the Sigma-1 receptor agonist is selected from: tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (A2-73), tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (A2-73 freebase), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (A1-41); tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (A1-41 freebase); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride (A19-144); 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine (A19-144 freebase); (1-(2,8-dimethyl- l-thia-3,8-diazaspiro(4.5)dec-3-yl)-3-(lH-indol-3-yl)propan-l- one) (A3-71); an enantiomer thereof, a crystal form thereof, a co-crystal form thereof, a pharmaceutically acceptable salt thereof, a crystal or co-crystal of the pharmaceutically acceptable salt thereof, and any combination thereof. 99 103396107.1Docket No: 085102-844842 PCT 76. The method of any one of claims 72-75, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in crystal Form III; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in amorphous form; (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in a crystal form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in amorphous form; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form III; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form IV; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrogen fumarate in crystal Form V; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine mesylate in crystal Form I; 100 103396107.1Docket No: 085102-844842 PCT tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine sulfate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine oxalate in crystal Form II; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine dihydrogen phosphate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine edisylate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine benzoate in crystal Form I; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form A; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrobromide in crystal Form B; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S5; tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine maleate in crystal Form S6; co-crystal Form CSII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with tartaric acid; co-crystal Form CSIII of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with citric acid; co-crystal Form CSIV of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine hydrochloride with malic acid; a co-crystal of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (-) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; a co-crystal of (+) tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride with zinc chloride; and 101 103396107.1Docket No: 085102-844842 PCT any combination thereof.

77. The method of any one of claims 72-76, wherein the administering is selected from an oral administration, a subcutaneous administration, an intravenous administration, an intraocular administration, an intradermal administration, an intramuscular administration, an intraperitoneal administration, an intratracheal administration, an inhalation administration, an intranasal administration, a sublingual administration, a buccal administration, a rectal administration, a vaginal administration, and a topical administration.

78. The method of any one of claims 72-77, wherein the period is about 12 weeks or less.

79. The method of any one of claims 72-78, wherein the period is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks.

80. The method of any one of claims 72-79, wherein the Sigma-1 receptor agonist is administered daily.

81. The method of any one of claims 72-80, wherein the Sigma-1 receptor agonist is selected from amorphous form of A2-73 free base, a crystal form of A2-73 freebase, A2-73 amorphous form, a A2-73 crystal form, and a A2-73 enantiomer.

82. The method of any one of claims 72-81, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine in Crystal Form I.

83. The method of any one of claims 72-82, wherein the Sigma-1 receptor agonist is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in Crystal Form I.

84. The method of any one of claims 72-83, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 1 mg to about 100 mg. 102 103396107.1Docket No: 085102-844842 PCT 85. The method of any one of claims 72-83, wherein the Sigma-1 receptor agonist is administered daily in an amount of about 5 mg to about 60 mg.

86. The method of any one of claims 72-83, wherein the Sigma-1 receptor agonist therapy is administered once daily in an amount of about 10 mg to about 50 mg.

87. The method of any one of claims 72-86, wherein the Sigma-1 receptor agonist comprises tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or tetrahydro- N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride in an oral solution, and wherein the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine or the tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride is administered once daily for a period of 12 weeks in an escalating dose regimen starting at about 5 mg to about 10 mg and ending at about 20 mg to about 30 mg.

88. The method of any one of claims 72-87, wherein the neurodevelopmental disease is Fragile X Syndrome.

89. The method of any one of claims 72-87, wherein the neurodevelopmental disease is Rett Syndrome.

90. The method of any one of claims 72-89, wherein the subject is a pediatric, a teenager, or an adult human.

91. The method of any one of claims 72-90, wherein the medial region comprises the left medial region or the right medial region.

92. The method of any one of claims 72-91, wherein the non-medial region comprises a cortical region or a lobe region.

93. The method of any one of claims 72-92, wherein the non-medial region comprises neocortex, allocortex, frontal lobe, temporal lobe, occipital lobe, parietal lobe, or any combination thereof. 103 103396107.1Docket No: 085102-844842 PCT 94. The method of any one of claims 72-93, wherein the EEG comprises scalp EEG or intracranial EEG.

95. The method of any one of claims 72-94, wherein assessing the disease risk further comprises considering one or more factors of the subject selected from genetic profile, age, family history of the disease, use of tobacco products, being exposed to radiation, being exposed to a toxic chemical, being exposed to a virus, or being exposed to a bacterium. 104 103396107.1

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