Gene delivery vehicles in the treatment of neurodegenerative diseases
View Patent ↗Currently no therapies that provide either protection or restoration of neuronal function for adult onset neurodegenerative diseases such as Parkinson's disease exist. Many clinical efforts to provide such benefits by infusion of neurotropic factors have failed. An alternative approach such as viral construct transduction may be used to directly activate the intracellular signaling pathways that mediate neurotrophic effects and induce axon growth. Viral construct transduction of dopaminergic neurons with a constitutively active human form of the p70S6K gene—hp70S6K (CA)—was shown to induce axon regeneration from living dopaminergic cell bodies that had no living axons.
1. A gene delivery vehicle comprising
(a) a gene hp70S6K (CA) identified by SEQ ID NO. 1 that encodes a constitutively active form of protein hp70S6K (delC/T389E) identified by SEQ ID NO. 2; and
(b) a 3′ UTR zip code or a short peptide sequence zip code that targets neurons.
2. The gene delivery vehicle of claim 1 , wherein the vehicle is a viral construct.
3. The viral construct of claim 2 , further comprising:
(c) a chicken β-actin (CBA) promoter;
(d) the gene hp70S6K (CA) identified by SEQ ID NO. 1, encoding a constitutively active form of protein hp70S6K (delC/T389E) identified by SEQ ID NO. 2, located downstream of the chicken β-actin promoter;
(e) a 3′ woodchuck post-transcriptional regulatory element WPRE (pBL)) located downstream of the gene; and
(f) a bovine growth hormone polyadenylation sequence (BGHpolyA) inserted before a 3′ inverted terminal repeat (ITR) sequence.
4. The viral construct of claim 1 wherein the short peptide sequence zip code is identified by SEQ ID NO.: 3.
5. The viral construct of claim 2 , wherein the viral construct is an adeno-associated construct.
6. The adeno-associated construct of claim 5 , comprising a serotype selected from the group consisting of AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-9, AAV-10, and AAV-11.
7. A pharmaceutical composition comprising the viral construct of claim 2 .
8. A kit comprising the pharmaceutical composition of claim 7 .
9. An AAV1 viral construct comprising (a) a gene hp70S6K (CA) identified by SEQ ID NO. 1 that encodes a constitutively active form of protein hp70S6K (delC/T389E) identified by SEQ ID NO. 2; and
(b) a 3′ UTR zip code or a short peptide sequence zip code that targets neurons.