GB221 Gene Therapy Enters First-in-Human CHARISMA Trial for Spinal Muscular Atrophy Type 1

A first-in-human clinical trial evaluating the investigational gene therapy GB221 for spinal muscular atrophy type 1 (SMA1) has begun dosing pediatric participants, according to a company announcement from Gemma Biotherapeutics (GEMMABio).¹

The phase 1/2 CHARISMA clinical trial (NCT07070999) is designed to assess the safety, tolerability, and preliminary efficacy of a next-generation adeno-associated virus (AAV) gene therapy administered via intracisterna magna (ICM) injection in infants with SMA1.² SMA1 is a severe form of SMA and typically presents within the first 6 months of life.

CHARISMA is a first-in-human clinical study evaluating GB221 in infants aged 2 weeks to younger than 12 months, including both symptomatic and presymptomatic participants.^1,2 The study will assess safety and tolerability as primary outcomes, with exploratory efficacy assessments including motor function and developmental milestones.

GB221 is delivered by direct injection into the cerebrospinal fluid via the cisterna magna, an approach intended to enhance central nervous system transduction while potentially reducing systemic exposure.¹ This route of administration differs from the intravenous delivery used by the currently approved gene therapy onasemnogene abeparvovec.³

The therapy uses an AAVhu68 vector encoding a codon-optimized survival motor neuron 1 (SMN1) gene under control of a modified expression cassette designed to limit excessive transgene expression.¹ According to the company, this design is intended to reduce risks of overexpression-related toxicities and sensory neuron injury that have been observed in preclinical and clinical gene therapy programs.

The trial is being conducted in Brazil and is expected to expand enrollment as additional sites become available. GEMMABio also reported that the United States FDA recently granted GB221 rare pediatric disease designation.

"I would like to express our gratitude for the young child and family who were courageous in being the first to accept our investigational gene therapy for SMA1," James M. Wilson, MD, PhD, the chiefe executive officer of GEMMABio CEO, and a member of the International Expert Advisory Board at Brazil's Casa dos Raros ("House of Rare"), said in a statement.¹ "We appreciate our steadfast partners at Fiocruz / Bio-Manguinhos, Brazil Ministry of Health, ANVISA (Brazil health regulatory agency), Casa dos Raros, Intrials, and the Hospital de Clínicas de Porto Alegre medical team who worked with us and who demonstrated the tremendous potential of international public-private partnerships with designated regional Research and Treatment Centers (RTCs). We anticipate expanding the CHARISMA clinical trial in Brazil and working together on future clinical trials for other rare disease gene therapies."

Notably, the treatment landscape for SMA has changed substantially over the past decade with the introduction of disease-modifying therapies, including the antisense oligonucleotide nusinersen, the oral SMN2 splicing modifier risdiplam, and the gene therapy onasemnogene abeparvovec.^3,5,6

Onasemnogene abeparvovec delivers a functional SMN1 gene via intravenous AAV9 vector and is approved in the US for pediatric patients with SMA younger than 2 years.³ Intrathecal or intracisternal delivery strategies have been explored to reduce peripheral exposure and enable lower vector doses while maintaining motor neuron transduction.

GB221 is an investigational AAV-based gene therapy designed to restore SMN1 expression in motor neurons through a one-time administration.¹ The central nervous system–targeted platform used in GB221 was originally developed at the University of Pennsylvania and licensed to GEMMABio. The university holds an equity interest in the company and may receive financial consideration related to intellectual property licensing.

"The medical team is monitoring the first patient carefully, hoping to see therapeutic benefit and progress towards developmental milestones," CHARISMA principal investigator Jonas Morales Saute, MD, PhD, who specializes in neurology and neurogenetics at the Hospital de Clínicas de Porto Alegre in Brazil, added to the statement.¹ "We are excited to leverage our experience in genetic diseases and clinical research to accelerate the development and evaluation of genetic medicines for other rare diseases."

REFERENCES

1. GEMMABio. GEMMABio Announces First Patient Dosed in CHARISMA Trial of GB221. February 26, 2026.
   https://www.prnewswire.com/

2. ClinicalTrials.gov. A Study to Evaluate GB221 in Participants With Spinal Muscular Atrophy Type 1 (CHARISMA). Updated 2026.
   https://clinicaltrials.gov/study/NCT07070999

3. US Food and Drug Administration. Zolgensma (onasemnogene abeparvovec-xioi) Prescribing Information.
   https://www.fda.gov/media/126109/download

4. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset SMA. N Engl J Med. 2017;377:1723-1732.
   https://www.nejm.org/doi/full/10.1056/NEJMoa1702752

5. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset SMA. N Engl J Med. 2018;378:625-635.
   https://www.nejm.org/doi/full/10.1056/NEJMoa1710504

6. Hordeaux J, Hinderer C, Buza EL, et al. Adeno-associated virus–induced dorsal root ganglion pathology. Hum Gene Ther. 2020;31(15-16):808-818.
   https://www.liebertpub.com/doi/10.1089/hum.2020.167