Huntington's disease (HD) is a rare neurodegenerative condition caused by increased CAG trinucleotide repeats in the HTT gene, on chromosome 4. The estimated global prevalence is 2.71 cases per 100,000 inhabitants. In Brazil, it is estimated that 13,000 to 19,000 people carry the gene and 65,000 to 95,000 are descendants at risk.

HD usually manifests itself in the fourth decade of life with motor, cognitive and behavioral symptoms, such as chorea. This condition profoundly affects quality of life and there is no treatment that can modify its course. Tetrabenazine is the only medication approved to control chorea.

A partnership between the Butantan Institute and Cellavita investigates the use of Human Dental Pulp Stem Cells (hDPSCs) to treat HD. NestaCell® was developed, a product based on these cells, which express high levels of BDNF, an important neurotrophic factor for neuronal survival.

Preclinical tests showed that NestaCell® is distributed to several organs, including the central nervous system, being well tolerated in toxicological tests in rats.

In phase I (SAVE) and phase II (ADORE) clinical trials, NestaCell® was administered to patients with HD. The results indicated a significant improvement in motor scores and functional capacity compared to placebo, demonstrating a clinically significant benefit.

NestaCell® also presented a good safety and tolerability profile, with few adverse events related to the product. The results support the conclusion that NestaCell® is safe and well tolerated in HD patients, within the doses tested.

This is a Phase III multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of Nestacell® in Huntington's Disease.

After signing the Informed Consent Form (ICF) the patients will perform the V-2 and V-1 screening procedures. In the V-2 the site collects personal data and a physician clinically confirms the HD diagnosis. The patient collects blood for CAG repeats and safety exams. Females with childbearing potential perform a urine pregnancy test. In the V-1 the investigator remotely reviews the results of the V-2 exams and authorizes the performance of the V-1 radiological exams (MRI and Total-Body PET Scan) in the radiology center.

In the V0, the PI and his team perform the baseline UHDRS and body weight assessments. The patient will be randomized to Nestacell® or placebo. Those weighing 50 to 67.9 kg will receive 100 million cells (or placebo) and those weighing ≥ 68 kg will receive 136 million cells(or placebo) per administration. The doses are based on the V0 weight assessment and will not change throughout the study unless the PI asks for safety reasons (for example, a relevant weight loss).

The V1 marks the first investigational product administration. It will happen in sites unrelated to those performing the outcomes evaluation by personnel specially trained to prepare and administer the investigational product. After the females with childbearing potential performe the urine pregnancy test, NestaCell® or placebo will be administered intravenously in three cycles of three-monthly administrations with a monthly interval between cycles (total of 9 administrations). The other administrations happen at visits V2, V3, V5, V6, V7, V9, V10, and V11. To assure blindness, UHDRS and other clinical evaluations will be carried out in the research center [by the principal investigator (PI)] while the administrations will be made in the Center for the Investigational Product Administration (CIPA). The outcome evaluations by the PI and his/her team happen at V4, V8, and V12, one month after the end of each cycle. In the V13, the patients will also be directed to the radiology center to repeat the MRI exam.

Each patient participates in the trial for approximately 14 months, two months for screening, and twelve months for investigational product administration and follow-up.

Inclusion Criteria:

1. Male or female;
2. Age from 18 to 55 years;
3. HD diagnostic confidence level (DCL) score of 3 or 4 at enrolment;
4. HD manifestations begin from 4 to 8 years before enrolment;
5. UHDRS Total Functional Capacity (TFC) from 7 to 12, suggesting mild-moderate functional impairment;
6. Body weight at the V -1 from 50 to 90 Kg;
7. CAG repeats from 40 to 50;
8. ICF signature.

Exclusion Criteria:

1. Juvenile Huntington's disease,

2. Concomitant epilepsy;

3. Decompensated psychiatric disorders;

4. History of a suicide attempt;

5. Other neurological or musculoskeletal disorders that might interfere with the assessments;

6. Prior use of gene or cell therapy.

7. Confirmed or suspected cancer within the last 1 year (except operated basal cell carcinoma);

8. History of allergy to imaging exams contrast, or bovine origin products;

9. Current or planned use of immunosuppressants;

10. Clinically significant changes in the safety exams, defined as;

    • Serum transaminases (ALT, AST) increased > 2.5 × upper limit of normality (ULN).
    • Absolute neutrophil count in peripheral blood < 3,000 cells/1 mm3.
    • Serum creatinine > 2 × age- and sex-specific ULN.
    • Positive serology for HIV 1 and 2 (Anti-HIV-1,2), HTLV I and II, HBV (HBsAg, Anti-HBc), HCV (anti-HCV-Ab), and FTA-ABS.
    • Amylase, Troponin I, CKmB increased > 2.0 × ULN.
    • Malignancy shown by the Total-Body PET Scan.
    • Glycated hemoglobin > 6.5%.
    • aPTT, TT, platelets > 2.5 x ULN.

11. Pregnancy, lactation, or pregnancy plan;

12. BMI less than 18.5 at enrolment;

13. Participation in a clinical trial within twelve months before inclusion;

14. History of surgical procedures aiming at improving symptoms of Huntington's disease, such as neural transplantations, lesions of the central nervous system, infusions of neurotrophic agents, or deep brain stimulation.

15. Any medical condition that makes the patient unsuitable for the study or increases the risk of participation at the investigator's discretion.

After the data analysis and presentation to the National Commission on Research Ethics, all data of the study will become public.

The trial will be two-armed double-blind (participant and investigator's team responsible for outcome assessments).