CNS Gene Therapy

CNS gene therapy offers the potential for transformative results

Gene therapy works by delivering a functional copy of the gene that is mutated, nonfunctional, or missing. While traditional drug development is especially difficult for neurodevelopmental disorders due to the blood-brain barrier and potential off-target effects, gene therapy delivered directly to the cerebrospinal fluid (CSF) presents a powerful method for achieving potentially long-term correction of diseases with a single treatment.

Principle of Gene Therapy

Illustration of the principle of gene therapy

A functional copy of the mutated, nonfunctional, or missing gene is introduced into target cells, where the new gene enters the nucleus. Once delivered, the new gene may confer stable, long-term expression of the new protein, offering effective, long-term disease treatment. There is also the potential benefit of cross-correction, where the protein secretes into neighboring cells, providing potential expansion of benefits to cells beyond those directly transduced by gene therapy.

AAV vectors in CNS Gene Therapy

Benefits of AAV-based gene therapies^*

Show promise in hard-to-target organs like the brain
Have the ability to transduce nondividing or slowly dividing cells like neurons
May potentially offer long-term disease treatment with a single administration
CNS-directed gene therapy via cerebrospinal fluid (CSF) likely provides the additional benefit of avoiding neutralizing antibodies (nAbs)
nAbs are produced by the body as a natural immune response to wild-type AAVs that are believed to significantly impede the efficacy of AAV vectors used in gene therapy

*There are risks associated with AAV-based therapies.

ICM image

CNS delivery utilizing intra-cisterna magna (ICM) administration

We are using ICM administration for our three most advanced clinical development programs to directly target the central nervous system.

In ICM administration, therapy is delivered directly to the CSF via injection into the cisterna magna, an area near the base of the skull, between the cerebellum and medulla
ICM has the potential to provide broad distribution of the gene therapy to the entire CNS
ICM is administered under anesthesia using modern neuroimaging to allow for precise delivery

ICM injection delivers the gene therapy vector directly to the CSF

Routes of vector gene therapy administration

Gurda et al, 2015; Hinderer et al, 2014, 2015, 2020; Pukeanas et al, 2021; Wang et al, 2019

A compelling approach: Direct delivery into the CSF may require lower doses of vector to reach clinically relevant transgene expression in the CNS, thus potentially reducing the overall immune response.

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