How capsid screening could unleash CNS genetic therapies at scale

Efforts to develop gene therapies for neurological disorders have been held back by the inability of current capsids to robustly transduce neurons in specific brain regions and at safe and cost-effective doses. The Children’s Hospital of Philadelphia’s Beverly Davidson identified an opportunity to address these problems in 2016, using direct routes of administration and conducting massively paralleled and unbiased screening to identify novel adeno-associated virus (AAV) variants that hone in on specific cell types in different brain regions of non-human primates (NHPs). Latus Bio was formed from Davidson’s pioneering research.

“Latus is about making vectors that are potent and safe with the broadest applicability so we can realize genetic therapies at scale,” said Davidson, founder and chair of the company’s scientific advisory board. “There’s been reluctance in the field because of durability issues and high levels of systemic exposures. Latus’ approach essentially mitigates all of that.”

Screening for capsids

The platform enables Latus to tailor screening of novel AAVs to parts of the brain and the exact cell types that are affected by a clinical disorder, identifying capsids matched with an intended clinical delivery route.

Latus’ patient-centric approach has led it to focus on direct administration into the central nervous system (CNS). Starting with parental AAV serotypes, the biotech generates diverse libraries of tens of millions of highly manufacturable capsids. Through successive rounds of screening in adult old-world NHPs, Latus identifies the most promising capsids for an application. Compared to naturally occurring AAV serotypes, Latus’ capsids transduce the NHP brain with greater tropism, using signficantly lower doses and injection volumes. Data are bolstered by in vitro evidence of superior transduction of human-induced pluripotent stem cell–derived neurons. Lower capsid doses further facilitate successful manufacturing and reduce the cost of goods.

“If you say to a patient with a devastating CNS disease, ‘There’s a therapeutic that could save your life but might harm your liver or spleen’, they want it delivered to their brain,” Jang-Ho Cha, CSO/CMO at Latus, said.

Direct routes of delivery, such as intraparenchymal and intracerebroventricular administration, minimize systemic toxicity and massively reduce the dose compared to peripheral delivery. The emergence of deep-brain stimulation as a frequently performed procedure means surgeons are comfortable with delivering therapies to the brain.

Precision delivery

Latus’ two lead programs illustrate the power of the platform. The biotech is developing a Huntington’s disease (HD) gene therapy based on its proprietary capsid, AAV-DB-3. HD damages the neurons in the striatum, leading Latus to target the deep brain. AAV-DB-3 transduces cells where it is delivered, and the capsid spreads throughout deep-brain structures and the cortex, transducing neurons in all brain regions that are critically impacted by HD (Fig. 1). In contrast, AAV5, a capsid used in other HD therapies, transduces neurons only where it is injected, using a method for delivering larger volumes of material into the brain.

AAV-DB-3’s pattern of spread allows Latus to use smaller volumes, delivered via fewer injections. These differences could translate into shorter procedure times, better safety profiles, and a smaller spike in neurofilament light chain, which is a protein the CNS releases in response to injury.

Latus’ other lead gene therapy uses its AAV-Ep+ capsid to target ependymal cells as well as neurons. Ependymal cells secrete proteins into the cerebrospinal fluid. Co-opting this function, AAV-Ep+ creates protein-synthesis factories within ependymal cells that bathe the brain in the therapeutic protein that is encoded by the gene therapy. The biotech is initially using the capsid to treat neuronal ceroid lipofuscinosis 2 (CLN2) disease. Children with the disease currently receive an enzyme-replacement therapy that entails a 4 h infusion every two weeks. Levels of the enzyme peak and trough, and symptoms progress, creating a need for a one-time gene therapy that provides a steady supply of protein. Latus’ potent AAV-Ep+ could achieve normal steady-state levels of the missing protein from a dose that is at least a log lower than those used with prior AAV therapies tested for CLN2 disease.

Partnering the platform

Latus is running investigational new drug (IND)-enabling studies and is on track to test its therapies in humans in 2025. Fast clinical proof-of-concept will support expansion to larger disease indications. Latus is developing capsids for pan-neuronal, spinal cord, cerebellum, eye, ear, and kidney indications, positioning it to treat genetic epilepsies, amyotrophic lateral sclerosis, Friedreich’s ataxia, and more.

Each capsid could be used in multiple diseases. The US Food and Drug Administration (FDA)’s platform technology designation will streamline the preclinical datasets required for future programs; but, even so, Latus can generate more capsids than any one company can develop.

As such, Latus is open to partnering. Collabo-rations with companies that have therapeutic area expertise are one possibility. Equally, the capsids can package a wide variety of cargoes, including genetic editors and gene writers, facilitating alliances with groups working on next-generation genetic modalities. Partnerships will further Latus’ focus on quickly realizing the potential of the platform to transform the lives of patients with unmet needs.