The Correction of Neurological Disease via Allele Specific Excision of Pathogenic Repeats (CASEPR) program, led by Dr. Jennifer Doudna, unites a diverse team of cross-expertise researchers focusing on developing innovative CRISPR-Cas-based therapeutics for Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS). The team’s collective innovation is channeled into three main goals to advance to Investigational New Drug (IND) status: creating an AAV-driven CRISPR therapy targeting the mutant HTT gene specific to HD, developing a similar approach for ALS focusing on allele-specific C9orf72 excision, and advancing a highly innovative and novel “Cas9 ribonucleoprotein monoparticle” CRISPR delivery method into neurons for HD. This groundbreaking research leverages CRISPR technology to selectively target and edit disease-causing genes, potentially revolutionizing the treatment of these debilitating neurodegenerative afflictions. The CASEPR program will impact nucleotide expansion diseases specifically, while having broader implications in advancing genome editing as a therapeutic approach to human genetic disease.

The Preclinical Genome Editing for Rare Neurological Diseases Program led by Dr. Cat Lutz, unites talented teams with unmatched expertise in base and prime editing, the development and production of AAV based vectors for treatment of rare disease, and preclinical animal modeling to develop, validate, and translate gene editing–based therapeutic solutions for four rare neurological genetic diseases: Spinal Muscular Atrophy, Friedreich’s Ataxia, Huntington’s Disease, and Rett Syndrome. We plan to merge these considerable assets and apply them to correct the underpinning genetic causes of these diseases, including repeat expansion diseases, in the relevant neurological tissues with the goal of advancing at least one of these strategies towards an IND submission.

Phenylketonuria (PKU), hereditary tyrosinemia type 1 (HT1), and mucopolysaccharidosis type 1 (MPSI) are inherited disorders of metabolism that cause debilitating and even life-threatening medical problems as early as birth. We seek to use a type of CRISPR gene editing technology, called base editing, to directly and permanently correct gene mutations or otherwise alter genes at the DNA level in the liver, either after or before birth—a “one-and-done” treatment strategy that could substantially improve the long-term health of patients with these diseases.

Prion disease is a rapidly fatal neurodegenerative disease with no available treatments. Prion disease occurs when the prion protein, a normally harmless protein, misfolds into prions, which are toxic. Evidence from multiple species and paradigms demonstrates that reducing the amount of prion protein in the brain is protective against prion disease, and should be safe. The first project seeks to test a genome editor targeted at PRNP, the prion protein gene. The goal of the editor is to change a single nucleotide in the PRNP gene sequence that would cause production of the prion protein to be interrupted early, leading to reduced levels in the brain. To be delivered effectively to brain cells, the editor construct must be packaged in a viral vector. Because the construct is large, it would need to be split between two vectors; only cells that receive both would be successfully edited. The second project seeks to test a genome editor that is similar to that described in Project 1, but has been modified to be small enough to fit in one viral vector. Similar to above, this goal of the editor would be to install a single nucleotide change in the PRNP gene sequence that would interrupt production of prion protein. The third project seeks to use an epigenome editor to turn the prion protein “off” by altering the DNA environment where the PRNP gene is located. The goal of the epigenome editor would be to change the three-dimensional packing of the DNA so that the PRNP gene becomes inaccessible, reducing the amount of the protein that is produced. The administrative core provides logistical support for the coordination of projects involving components from multiple labs. The resource core designs, develops and produces all of the viral vectors that allow us to deliver our genomic and epigenomic editors. Together, our projects aim to develop a one-time therapy for prion disease by targeting the single genetic root cause of disease.