Our Approach
JayaBio’s platform is based on the groundbreaking discovery that carriers (heterozygotes) of loss-of-function mutations in genes for lysosomal enzymes have an increased risk of neurodegeneration, including early onset of symptoms.
Our science challenges the old dogma that carriers of lysosomal enzyme gene defects are normal throughout life and provides a conceptual and practical framework to treat neurodegeneration associated with these heterozygous mutations. Furthermore, our studies show that Alzheimer’s is not a homogenous disease, and most likely, there are several patient subpopulations, each with its distinct disease etiology.
JayaBio’s mission is to fulfill a promise of victory over neurodegenerative diseases by identifying and effectively targeting the relevant pathways involved in the etiology of these debilitating diseases.
Autophagy-Lysosomal Pathway
Impaired autophagy-lysosomal pathway (ALP) is a key component in the etiology of genetically defined CNS dysfunction. Lysosomes, are subcellular organelles responsible for the normal degradation and turnover of cellular components and aggregation-prone proteins.
Deficits in the autophagy-lysosomal pathway (ALP) result in protein aggregation, the generation of toxic protein species, and the accumulation of dysfunctional organelles, which are hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD)¹.
Lysosomal degradation plays a critical role, as the degradation of autophagosomal cargo cannot proceed without successful fusion to an available and functional lysosome². Lysosomal function declines with age and likely contributes both to the aging process itself as well as the development of age-related diseases such as neurodegenerative diseases and cancer²,³.
Emerging evidence suggests that defects in certain lysosomal enzyme genes are associated with various neurodegenerative diseases such as Parkinson’s Disease⁴, Frontotemporal Dementia⁵, and Alzheimer’s Disease⁶.
Lysosomal Gene Targets for Alzheimer’s Disease
Our team discovered that pathogenic mutations in certain lysosomal genes are enriched in neurodegeneration, including Alzheimer’s disease. This haploinsufficiency negatively affects the processing of amyloid precursor protein (APP) by shifting processing from a non-amyloidogenic to an amyloidogenic pathway.
In an animal model of Alzheimer’s disease, these mutations dramatically exacerbate the formation of amyloid plaques and severely reduce lifespan. Our gene therapy targets the upstream effector pathways rather than the historical approach of targeting downstream markers of the disease (Aβ plaques, Tau tangles, etc.). A single intracerebroventricular injection (ICV) of an AAV9 vector carrying the correct copy of the gene rescued the disease phenotype by significantly reducing plaque formation, increasing animal lifespan and improving cognition.
To date, we have validated five lysosomal gene targets in vivo. This discovery differs from previously reported genetic mutations, which increase the overall level of APP, leading to the formation of Aβ plaques. Furthermore, this illustrates that Alzheimer’s is not a homogenous disease, and most likely, there are several patient subpopulations, each with its distinct disease etiology, highlighting the need for a precision medicine approach in Alzheimer’s disease and other genetically-defined neurodegenerative conditions.
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1. Martini-Stoica H, et al., (2016) Trends Neurosci 39(4):221-234
2. Levine B, Kroemer G, (2019) Cell 176(1-2):11-42
3. Hansen M, et. al., (2018) Nature Rev Mol Cell Biol, 19(9):579-593
4. Sidransky E, et al., (2009) N Engl J Med 361(17):1651-61.
5. Baker M, et al., (2006) Nature, 442(7105):916-9
6. Lopergolo D, et al., (2023) J Med Genet, Epub ahead of print
Our Lead Therapy
JB111, our lead therapy, is an experimental CNS-directed AAV9-mediated PPT1 gene therapy currently being developed for neurodegeneration associated with PPT1 haploinsufficiency (carrier status for loss-of-function mutations in palmitoyl protein thioesterase-1 gene or PPT1 heterozygosity). JB111 showed very promising results in the animal model of PPT1-associated Alzheimer’s disease (5XFAD mouse harboring PPT1 heterozygous allele). Single intracerebroventricular (ICV) injection of JB111 resulted in a significantly increased life span and improved cognitive performance.
Our Platform
Jaya Biosciences is a platform company with multiple shots on goal. Our personalized neurodegenerative diseases gene discovery platform (NGeneP) consists of Target Identification, Target Validation, and Therapy Development. NGeneP uses proprietary genomic algorithms to identify genetic mutations that are enriched in Alzheimer’s and other neurodegenerative diseases. Identified gene targets are then validated in vivo to assess the effects of loss-of-function mutations on biochemical pathways critical in the development of diseases of interest. Once the target is validated, a gene vector carrying the correct copy of the gene or another appropriate therapy is tested in the animal model of the disease to assess the efficacy.
To date, we validated, in vivo, five different lysosomal enzyme genes (PPT1, NAGLU, GALC, IDUA, GUSB) that significantly affect amyloid precursor protein (APP) processing and favor pro-amyloidogenic pathway. We continue to expand the pipeline with additional ongoing discovery programs.
