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1. WO2020113338 - METHOD OF REDUCING NEURONAL MICROTUBULE BINDING PROTEIN TAU (TAU) LEVELS

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[ EN ]

CLAIMS:

1. A method of reducing neuronal microtubule binding protein Tau (Tau) levels, promoting neuronal Tau degradation and/or promoting neuronal survival, in a subject in need thereof comprising contacting the subject's neurons with an effective amount of an agent that increases a long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity, whereby neural Tau levels is reduced in the presence of the agent, the neuronal Tau degradation is promoted and/or the neuronal survival is promoted as compared to in the absence thereof.

2. The method of claim 1 , wherein the long PTB Numb isoform is Numb-72 or Numb-66.

3. The method of claim 1 , wherein the long PTB Numb isoform is Numb-72.

4. The method of any one of claims 1 to 3, wherein the neurons are retinal neurons.

5. The method of any one of claims 1 to 4, wherein the subject has a tauopathy or a Tau-associated optic neuropathy.

6. The method of claim 5, wherein the subject has a Tau-associated optic neuropathy.

7. The method of any one of claims 1 to 3, wherein the neurons are motoneurons.

8. The method of claim 7, wherein the subject has a paralysis.

9. The method of any one of claims 1 to 8, wherein the reducing is performed by administration of the long PTB Numb isoform in a gene delivery vector.

10. The method of claim 9, wherein the gene delivery vector is a viral vector.

1 1. The method of claiml O, wherein the viral vector is an adeno-associated vector (AAV).

12. The method of claim 1 1 , wherein the AAV of serotype 2.

13. A method for stratifying a subject having a pathological condition associated with toxic intraneuronal Tau accumulation, comprising detecting a long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity in the subject's neurons, wherein said detecting enables the stratification of the subject, preferably wherein when a reduced long PTB Numb isoform expression and/or activity is detected as compared to a reference long PTB Numb isoform expression and/or activity, the subject is included in a clinical trial for an agent that increases the long PTB Numb isoform expression and/or activity.

14. The method of claim 13, wherein the pathological condition associated with intraneuronal Tau accumulation is a tauopathy, a Tau-associated optic neuropathy or a motor deficit.

15. The method of claim 14, wherein the tauopathy is Alzheimer's disease.

16. A composition comprising (a) an agent that increases neuronal long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity; and (b) (i) a pharmaceutically acceptable carrier; (ii) at least one further therapeutic agent; or (iii) a combination of (i) and (ii).

17. The composition of claim 16, comprising at least one further therapeutic agent.

18. The composition of claim 17, wherein the at least one further therapeutic agent comprises an acetylcholinesterase inhibitor.

19. A kit or package comprising (a) an agent that increases neuronal long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity; and (b) (i) instructions to use the agent to treat a pathological condition associated with intraneuronal Tau accumulation; (ii) at least one further therapeutic agent; or (iii) a combination of (i) and (ii).

20. The kit or package of claim 19, comprising at least one further therapeutic agent.

21. The kit or package of claim 20, wherein the at least one further therapeutic agent comprises an acetylcholinesterase inhibitor.

22. A kit or package comprising (a) a reagent for determining a long phosphotyrosine-binding (PTB) Numb isoform expression and/or activity; and (b) (i) a reagent for determining Tau expression and/or activity; (ii) instructions for the prognosis and/or diagnosis of pathological condition associated with intraneuronal Tau accumulation; or (iii) a combination of (i) and (ii).