Gluconeogenesis as a pro-survival treatment for neurons under stress

A series of AAV-based gene therapy approaches to reprogram certain metabolic enzymes in rod and cone cells in the eye to promote survival in degenerative conditions such as retinitis pigmentosa. Additionally, an independent series of such vectors expressing HDAC genes and/or HIF1alpha variants to achieve the same.

Given the heterogeneity of retinal degenerative disease identifying a common pathway for how degenerating cells die has led to insights into how cell death can be prevented. The Cepko lab has been able to show with single injections in a mouse model for RP (rd1), that introducing certain genes that ultimately modulate glycolysis/gluconeogenesis in cone photoreceptor cells can prevent cell death and maintain visual function weeks after control vector-injected animals have become blind. This concept has been validated by 2 separate gene-therapy based interventions in the same mouse model for retinitis pigmentosa. By preventing retinal cell death, rather than addressing the molecular lesion(s) that contributed to disease, retinal degeneration can be stopped and visual function can be maintained in a generic fashion, independently of the type of disease gene.

The Cepko lab is currently working to optimize vector/gene combinations and is seeking collaborators that can help drive the program into clinic development.


Reduced viability of rod and cone photoreceptor cells is associated with various retinal disorders, e.g. retinitis pigmentosa. Although most mutations that cause retinitis pigmentosa are in rod photoreceptor-specific genes, cone photoreceptors also die as a result of such mutations. Retinitis pigmentosa is a family of inherited retinal degenerations (RD) that is currently untreatable and frequently leads to blindness. Affecting roughly 1 in 3,000 individuals, it is the most prevalent form of RD caused by a single disease allele (RetNet). The phenotype is characterized by an initial loss of night vision due to the malfunction and death of rod photoreceptors, followed by a progressive loss of cones.

In January 2009, the Cepko lab published findings linking HDAC4 activity with survival in normal and diseased retinas (B. Chen and C. Cepko 2009 Science 323 p. 256). Hif1? activity was shown to be necessary for HDAC4 mediated survival activity and a stabilized allele of HIF1alpha was shown to be sufficient for rod survival. HIF1alpha can transcriptionally regulate glycolytic pathways. Similarly, changes in the insulin/mTOR pathway coincide with the activation of autophagy in cones and manipulation of the pathway via systemic administration of insulin can modulate the rate of cone death (Punzo et al. 2009 Nat. Neuro. 12(1) p. 44). Thus, two seemingly separate observations both implicating aspects of nutrient sensing or glucose homeostasis in cones, led to a testable hypothesis. If cones were dying because they were starving, interventions that perturb glucose homeostasis may rescue or delay cell death.

The Cepko lab has created a gene therapy that could prevent the decline of vision in degenerative disease independent of etiology. Given the recent success in treating Leber’s Congenital Amaurosis in humans with an AAV-based vector (Bainbridge et al. 2008 NEJM 358(21), Maguire et al. 2008 NEJM 358(21)) this Cepko lab invention could expand treatment options for degenerative diseases in the eye.

Intellectual Property Status: Patent(s) Pending