Sangamo Therapeutics : ST-503 nonclinical safety studies evaluating zinc finger repressors regulating the expression of the Nav1.7 gene for treatment of small fiber neuropathy

Published: 2026-05-12 06:20:08 ET SGMO

Published on 05/12/2026 at 06:20 am EDT

ST-503 nonclinical safety studies evaluating zinc finger repressors regulating expression of

the Nav1.7 gene for treatment of small fiber neuropathy

Kathleen Meyer,Toufan Parman, Kenneth Kennard, Marina Falaleeva, Annemarie Ledeboer, Carolyn Gasper,Yonghua Pan, Jing Hu, Madalena Nguyen,Veronica Bonazza, Liching Cao, Yanmei Lu and Mohammad Samie

Poster #1309

ST-503 is an investigational AAV9 gene therapy, encoding an engineered zinc finger repressor (ZFR) targeting the SCN9A gene for treatment of small fiber neuropathy. SCN9A codes for Nav1.7, a voltage gated sodium channel, which is involved in various inherited pain-related disorders and has emerged as a promising target for central neuropathic pain therapies. The expression of the ZFR is under the control of a neuron-specific promoter. The objective of this novel therapy is to target the dorsal root ganglion nociceptive neurons, express the ZFR, which will selectively bind and repress SCN9A gene expression, and then ultimately reduce production of Nav1.7 sodium channels and diminish perception of neuropathic pain. To support ST-503 clinical development, two key GLP studies are reported here

Pre-Implantation

Post-Implanation

Control

Untreated Females

Pre-Implantation

Post-Implanation

0 10 20 30 40 50 60

% Loss

Control

Treated Females

0 10 20 30 40 50 60

% Loss

Clinical observations, body weights, gravid uterine weights, macroscopic pathology and ovarian and uterine examinations

Male and female reproductive performance

Sperm evaluations

Fetal morphological data

Fetal external, visceral and skeletal examinations

including a 6-month pharmacology and toxicology study in nonhuman primates (NHP) and a developmental and reproductive toxicology (DART) study in mice. Assessments for AAV integration and germline transmission risk were included in the DART study. These studies were part of the nonclinical program supporting the First-in-Human (FiH) clinical study.

1E+13, 6E+13

or 9E+13 vg/animal

ST-503 was administered as a one-time intrathecal (IT) injection at dose levels of 1E+13, 6E+13 and 9E+13 vg/animal to cynomolgus monkeys.

Pharmacology assessments at 6 months (bulk ZFR and SCN9A mRNA in dorsal root ganglia (DRG)) and trigeminal ganglia showed intended targeted SCN9A gene repression.

Group Number

F0 Female Treatment

F0 Male Treatment

Necropsy (Day)

Tissue Type

No. of Animals

Mean Copies/µg gDNA

Vehicle

Untreated

GD 18

Liver

BLOQ

Untreated

Vehicle

GD 18

Liver

BLOQ

AAV9.m95676

Untreated

GD 18

Liver

BLOQ

Untreated

AAV9.m95676

GD 18

Liver

BLOQ

BLOQ - below the level of quantification

Total of 3,144 unique and mappable integration sites (IS) detected in ~29 million sequencing reads.

Safety assessment at 6 months showed no ST-503-related adverse effects on parameters: clinical observations, food consumption, body weights, clinical pathology (including liver enzymes), coagulation, neurological exams, ECG, heart rate and blood pressure measurements, nerve conduction velocity, macroscopic pathology or microscopic pathology of peripheral tissues. Histopathological findings consistent with AAV class effects in DRGs, spinal cord and/or

Maximum intended AAV9 clinical

intrathecal dose was intravenously administered to male and female C57BL/6 mice 4 weeks prior to

AAV9mZFR (5.7E+12 vg/kg) or Vehicle Dosed female paired with untreated male Dosed male paired with untreated female

Estimated average frequency of 1.30 ± 0.17 IS/1000 cells.

IS analysis shows low levels of vector integration, a polyclonal integration profile, no evidence of clonal expansion, no strong association with cancer-associated genes and supports a very low

trigeminal ganglia (TG) (including minimal to mild mononuclear infiltrates, glial cell aggregates, axonal degeneration;

minimal neuronal degeneration in DRG) were not considered dose-limiting for the FiH study.

mating with untreated animals.

Mouse surrogate ZFRs (AAV9mZFR) were designed to target the mouse

Pre-Mating Mating

Pregnancy

GD 0-18

Gestation Day (GD) 18 Necropsy

risk of hepatocellular carcinoma.

Figure courtesy of ProtaGene

Scn9a gene due to lack of target

sequence homology between mouse and human genes coding for Nav1.7.

~ 4 wks

~ 2 wks

2 wks

Estrous Check

F0 (DART and AAV

integration)

F1 litters (DART & germline transmission)

6-month GLP study in NHPs showed anticipated targeted repression of SCN9A in DRGs and trigeminal ganglia (up to

Standard developmental and reproductive toxicology assessments conducted for parental animals and fetal offspring.

Germline transmission risk assessment conducted on fetal liver DNA of offspring.

AAV integration site analysis of maternal liver DNA conducted using Targeted Enrichment Sequencing (TES).

60% bulk tissue repression) and was well tolerated with no dose-limiting toxicological findings.

- Supported dose selection for the FiH study in patients with small fiber neuropathy.

A single IV dose of AAV9 mouse surrogate ZFR at 5.71 x 1012 vg/kg showed no test article-related adverse effects on fertility or embryo-fetal development parameters, and there was no evidence of AAV germline transmission to

offspring.

Control Treated Males

150

% Value

100

Mating

Fertility

Pregnancy

150

% Value

100

Pregnancy

Mating

Control

Untreatd Females

150

% Value

100

Control 15

Control

Untreated Females

Control

ST-503-Treated Females

Average per Female

Treated Females 15

Corpora Lutea

Implantations

Resorptions

Early Resorpstions

Late Resorptions

Fetuses

Live Fetuses

Dead Fetuses

Corpora Lutea

Implantations

Resorptions

Fetuses

Live Fetuses

Dead Fetuses

Mating

Fertility

Pregnancy

0 0

- Based on these results, ZFR-mediated repression of Nav1.7 is not expected to pose a fertility, reproductive, or

vertical transmission risk to women of childbearing potential or men.

AAV9 integration profile in liver tissue does not raise concern for risk of liver tumor formation given that there was no integration detected into the Rian locus, no expanded clones detected in the vicinity of cancer-associated genes, and the overall random integration pattern.

These studies were part of the nonclinical safety evaluation program supporting ST-503 clinical development.

Heart Rate

Early Resorpstions

Late Resorptions

-2

Control

Treated Males

100 1

% Sperm Motility

% Total Sperm

Normal

Abnormal

Abnormal Head

Detached Head

Abnormal Tail

Detached Tail

Control ST-503

With Live Fetuses

With Resorptions

With All Fetuses Nonviable

With Normal Placenta

With Live Fetuses

With Resorptions

With All Fetuses Nonviable

With Normal Placenta

Sperm Morphology

100

Control

Untreated Females

% Untreated Females

Pregnant

100

Control ST-503-Treated Females

% Treated Females

Pregnant

Engineered zinc finger repressors induce a prolonged and selective repression of SCN9A in nociceptors of nonhuman primates. Samie et al, 2026, Science Translational Medicine 2026 Mar 25;18(842):eadu0217;1-18.

We would like to acknowledge our CRO partners Charles River Laboratories (toxicology studies) and ProtaGene

*Mating Index = (# males with evidence of mating / # males paired) x 100; Fertility Index = (# males impregnating a female

/ #males paired) x 100; Pregnancy Index = (# males impregnating a female / # males with evidence of mating) x 100

(AAV integration assessment) who supported this work.This study was sponsored by Sangamo Therapeutics.

Disclaimer

Sangamo Therapeutics Inc. published this content on May 12, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 12, 2026 at 10:19 UTC.