Objective: We have developed a modified frameless stereotaxic system for viral vector delivery of gene therapy in pediatric movement disorder patients with congenital enzyme deficiency.

Background: Gene therapy in pediatric movement disorder patients with various genetic disorders involving the brain, is regarded as the most promising therapeutic tool for these patients. To achieve success in certain gene therapy, the major issue is the safe and efficient delivery of viral vectors into specific target brain region, and stereotaxic surgery is the essential step in this therapy. However, there is still limited experiences in stereotaxic surgery used for gene therapy in the very young aged patients (2~6 years of age). Using traditional stereotaxic techniques and procedures in this special group of patients are highly challenging in many aspects, including the small size of cranium, the maturity of skull bone and even the deformity of skull and brain due to bed ridden condition. In contrast, the modified frameless stereotaxy, utilizes light-weighted materials to build a small-sized but highly accurate stereotaxic device, assisted with computer calculation of target, is highly beneficial for pediatric patients with the need of gene therapy.

Methods: The system consists of newly designed frameless stereotaxic instruments and surgical procedures, in combination with existed frameless stereotaxic and computer-assisted planning/navigation system. The fiducial marker unit specially designed for fragile skull of pediatric patients are composed of an adhesive pad and a 4-mm long screw. A lollipop-like stereotactic stabilizer is introduced to anchor the frameless stereotaxic apparatus just above the burr hole during surgery.

Results: This modified frameless stereotaxic system has been used in gene therapy with bilateral putaminal injection of adeno-associated virus (AAV) vector AAV2-hAADC in 27 pediatric movement disorder patients with aromatic L-amino acid decarboxylase (AADC) deficiency, ages between 20 months and 6 years. Each patient received post-operative MRI study to confirm the successful injection of the AAV vector without intra-cerebral hemorrhage or other complication. We also performed fluoro-dopa (FDOPA) PET scan pre- and post-operatively and there is significant increase in the FDOPA uptake in both striatum after the surgery.

Conclusions: This modified frameless stereotaxic system is suitable for stereotaxic gene therapy or other stereotaxic procedures in pediatric movement disorder patients as early as 2 years of age.

References: Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, Snyder RO, Byrne BJ, Tai CH, Wu RM. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012 May 16;4(134):134ra61. doi: 10.1126/scitranslmed.3003640. PubMed PMID: 22593174.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modified-frameless-stereotaxy-for-gene-therapy-in-pediatric-movement-disorder-patients/