Targeting the spinal cord and the surrounding “spine” environment is critical for treating motor neuron diseases (like ALS and SMA), chronic pain, and spinal cord injuries. The primary challenge is the Blood-Spinal Cord Barrier (BSCB) and the dense distribution of cells across the long vertebral column.

Quick Legend: Administration Routes

• IT (Intrathecal): Injection into the cerebrospinal fluid (CSF) via lumbar puncture. Bypasses the blood-spinal barrier; provides broad distribution.
• IP (Intraparenchymal): Direct injection into the spinal cord tissue (grey/white matter). Highly localized; surgically invasive.
• ICM (Intra-cisterna Magna): Injection into the CSF at the base of the skull. Excellent for “top-down” coverage of the cervical cord and brainstem.
• IV (Intravenous): Systemic delivery. Least invasive but requires capsids that can cross the BSCB (like AAV9).

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1. Natural AAV Serotypes

Serotype	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV9	Motor Neurons (MNs), Astrocytes	IV / IT / ICM	The Clinical Benchmark. • One of the few natural capsids that crosses the BSCB from the blood. • Used in Zolgensma for Spinal Muscular Atrophy. • IT Delivery: Provides excellent, widespread transduction of motor neurons throughout the cord.
AAV6	Motor Neurons, Astrocytes	IT / IP	High Potency. • Shows high affinity for motor neurons when delivered via the CSF. • Often outperforms AAV9 in specific rodent models for localized intraparenchymal injections.
AAV8	Dorsal Horn Neurons, Astrocytes	IP / IT	Sensory Specialist. • Known for efficient transduction of neurons in the dorsal horn (sensory processing area) when injected directly into the spinal tissue. • Less likely than AAV9 to spread to the brain or DRG from the injection site.
AAV1 / AAV2	Interneurons, Local Neurons	IP	Localized Tools. • Frequently used for circuit mapping; AAV1 exhibits strong anterograde (forward-moving) transport along spinal axons.
AAVrh10	Motor Neurons, Glia	IT / ICM	Derived from non-human primates; similar to AAV9 in its ability to reach the spinal cord via CSF, but with potentially different immunogenicity profiles.

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2. Engineered & Synthetic Capsids

Designed to “flood” the spinal cord from the blood or CSF with much higher efficiency than natural serotypes.

Variant	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV-PHP.eB	Neurons, Astrocytes (CNS-wide)	IV	The “Super-AAV9”. • Engineered via directed evolution to cross the blood-brain/spinal barrier with 40–100x the efficiency of AAV9. • Provides massive, whole-spine transduction from a single peripheral vein injection.
AAV-PHP.S	Dorsal Root Ganglia (DRG)	IV	Peripheral Nerve Specialist. • Designed to target the sensory nerves entering the spine. • Essential for treating chronic pain or sensory neuropathies while avoiding the central brain.
AAV2-retro	Projection Neurons	IP / Muscle	The Backwards Traveler. • Specifically engineered for retrograde transport. If injected into a muscle, it travels up the axon to hit the motor neuron cell body in the spine.
AAV-Anc80	Spinal Neurons, Glia	IT / IV	A synthetic ancestral capsid that shows robust and widespread spinal transduction, often with lower pre-existing immunity in the human population.

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3. Tropism by Target Cell

If you are targeting a specific spinal population, start here:

• Lower Motor Neurons (Ventral Horn): AAV9 (IT/IV) or AAV2-retro (via Muscle).
• Sensory Neurons (Dorsal Horn/DRG): AAV8 (IP) or AAV-PHP.S (IV).
• Astrocytes / Glial Scar: AAV9 or AAV-PHP.eB (paired with a GFAP promoter).
• Widespread “Whole-Spine” Delivery: AAV9 or AAV-PHP.eB (via IV/IT).

Critical Factor: The Direction of Flow

When targeting the spine, the physical movement of the vector is key:

1. CSF Dynamics: When injecting Intrathecally (IT), the vector moves with the CSF. To hit the “upper” spine (cervical), Trendelenburg positioning (tilting the patient head-down) is sometimes used to help the virus float toward the neck.
2. Axonal Transport:
   • Anterograde (AAV1): Moves from cell body to axon terminal.
   • Retrograde (AAV2-retro): Moves from axon terminal back to the cell body. This is vital for “picking up” the virus from a muscle and bringing it into the spine.