Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50

This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity.

The secondary outcome will be a preliminary exploration of efficacy of the treatment.

MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg.

The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.


Eligibility Criteria:
Inclusion Criteria:

* Age \< 5 years old
* Confirmed diagnosis of SPG50 disease by:
* Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the AP4M1 gene
* Clinical history or examination features consistent with SPG50 and that include neurologic dysfunction
* Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study
* Subject able to comply with all protocol requirements and procedures

Exclusion Criteria:

* Inability to participate in study procedures (as determined by the site investigator)
* Presence of a concomitant medical condition that precludes lumbar puncture (LP) or use of anesthetics
* History of bleeding disorder or any other medical condition or circumstance in which lumbar puncture is contraindicated according to local institutional policy
* Inability to be safely sedated in the opinion of the clinical anesthesiologist
* Active infection, at the time of dosing, based on clinical observations
* Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
* Inability of the patient to undergo MRI according to local institutional policy
* Inability of the patient to undergo any other procedure required in this study
* The presence of significant non-SPG50 related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
* Have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study.
* Enrollment and participation in another interventional clinical trial
* Contraindication to MELPIDA or any of its ingredients
* Contraindication to any of the immune suppression medications used in this study
* Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin \> 3 × Upper Limit of Normal (ULN), creatinine ≥ 1.5 mg/dL, hemoglobin \[Hgb\] \< 6 or \> 20 g/dL; white blood cell (WBC) \> 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded